The structure and functions of the endothelium. Vascular endothelium as an endocrine network Functions of the vascular endothelium
The owners of the patent RU 2309668:
SUBSTANCE: invention relates to medicine, namely to functional diagnostics, and can be used for non-invasive determination of endothelial function. To do this, the transmural pressure in the limb is reduced, the amplitudes of plethysmographic signals are recorded at various pressures. The pressure at which the amplitude of the plethysmographic signal is maximum is determined, while the pressure is reduced to a value corresponding to a given percentage of the maximum amplitude, an occlusive test is performed, during which in a cuff applied proximally from the located area of the limb. Next, a pressure is created that exceeds the systolic pressure of the subject by at least 50 mm Hg, while occlusion is carried out for at least 5 minutes. The device includes a sensor unit made of two channels and capable of recording pulse curves from peripheral arteries. A pressure generating unit configured to create stepwise increasing pressure in the cuff. An electronic unit configured to determine the cuff pressure corresponding to the maximum amplitude of the plethysmographic signal, and control the pressure generation unit to set the pressure in the cuff corresponding to the amplitude of the plethysmographic signal, which is a predetermined percentage of the maximum amplitude, while the sensor unit is connected to the electronic unit, to the output of which is connected to the pressure generation unit. The claimed invention improves the reliability of endothelial function assessment regardless of the patient's blood pressure. 2 n. and 15 z.p. f-ly, 6 ill.
The invention relates to medicine, namely to functional diagnostics, and makes it possible to detect the presence of cardiovascular diseases at an early stage and to monitor the effectiveness of the therapy. The invention will make it possible to assess the state of the endothelium and, on the basis of this assessment, solve the issue of early diagnosis of cardiovascular diseases. The invention can be used when carrying out a large-scale medical examination of the population.
Recently, the problem of early detection of cardiovascular diseases has become increasingly important. For this, a wide range of diagnostic tools and methods are used, described in the patent and scientific literature. Thus, US patent No. 5,343,867 discloses a method and device for the early diagnosis of atherosclerosis using impedance plethysmography to identify features of the pulse wave in the vessels of the lower extremities. It was shown that the blood flow parameters depend on the pressure applied to the studied artery from outside. The maximum amplitude of the plethysmogram is largely determined by the transmural pressure, which is the difference between the arterial pressure inside the vessel and the pressure applied outside with the help of a tonometer cuff. The maximum signal amplitude is determined at zero transmural pressure.
From the standpoint of the structure and physiology of arterial vessels, this can be represented as follows: the pressure from the cuff is transferred to the outer wall of the artery and balances the intra-arterial pressure from the inner wall of the artery. At the same time, the compliance of the arterial wall increases sharply, and the passing pulse wave stretches the artery by a large amount, i.e. the increase in the diameter of the artery at the same pulse pressure becomes large. This phenomenon is easy to see on the oscillometric curve taken during the registration of blood pressure. On this curve, the maximum oscillation occurs when the cuff pressure equals the mean arterial pressure.
US Pat. No. 6,322,515 discloses a method and device for determining a number of parameters of the cardiovascular system, including those used to assess the state of the endothelium. Here, photodiodes and photodetectors were used as a sensor for determining the pulse wave; an analysis of photoplethysmographic (PPG) curves recorded on the digital artery before and after the test with reactive hyperemia was carried out. When these curves were recorded, a cuff was placed on the finger over the optical sensor, in which a pressure of 70 mm Hg was created.
US Pat. No. 6,939,304 discloses a method and apparatus for non-invasive evaluation of endothelial function using a PPG sensor.
US Pat. No. 6,908,436 discloses a method for assessing the state of the endothelium by measuring the propagation velocity of a pulse wave. For this, a two-channel plethysmograph is used, the sensors are installed on the phalanx of the finger, occlusion is created using a cuff located on the shoulder. The change in the state of the arterial wall is assessed by the delay in the propagation of the pulse wave. A delay value of 20 ms or more is considered as a test confirming the normal function of the endothelium. The determination of the delay is carried out by comparing with the PPG curve recorded on the arm, on which the occlusion test was not performed. However, the disadvantages of the known method is the determination of the delay by measuring the displacement in the region of the minimum immediately before the systolic rise, i.e. in a region that is highly variable.
The closest analogue to the claimed method and device are the method and device for non-invasive determination of changes in the physiological state of the patient, described in RF patent No. 2220653. A known method consists in monitoring peripheral arterial tone by placing a cuff on the pulse sensors and increasing the pressure in the cuff to 75 mm Hg, then measuring blood pressure with increasing pressure in the cuff above systolic for 5 minutes, further recording the pulse wave by the PPG method on two hands, after which an amplitude analysis of the PPG curve is carried out in relation to the measurements obtained before and after clamping, the increase in the PPG signal is determined. The known device includes a sensor for measuring pressure with a cuff, a heating element for heating the surface of the located area of the body and a processor for processing the measured signals.
However, the known method and device do not provide high reliability of the studies due to the low accuracy of measurements and their dependence on fluctuations in the patient's pressure.
Endothelial dysfunction occurs in the presence of such risk factors for cardiovascular diseases (CVD) as hypercholesterolemia, arterial hypertension, smoking, hyperhomocysteinemia, age, and others. It has been established that the endothelium is a target organ in which risk factors for the development of CVD are pathogenetically realized. The assessment of the state of the endothelium is a "barometer", a glance at which allows early diagnosis of CVD. Such diagnostics will make it possible to move away from the approach when it is necessary to conduct a series of biochemical tests (determination of the level of cholesterol, low and high density lipoproteins, homocysteine, etc.) to identify the presence of a risk factor. It is economically more reasonable to screen the population at the first stage to use an integral indicator of the risk of developing the disease, which is the assessment of the state of the endothelium. Assessment of the state of the endothelium is also extremely relevant for the objectification of the therapy.
The task to be solved by the claimed inventions is to create a physiologically substantiated, non-invasive method and device for reliably determining the state of the endothelial function of the examined patient, providing a differentiated approach depending on the patient's condition and based on a system for converting, amplifying and recording PPG signal under the action of an optimal the value of the given pressure or the force locally applied to the located artery before and after the occlusion test.
The technical result, which is achieved when using the claimed device and method, is to increase the reliability of endothelial function assessment, regardless of the patient's blood pressure.
The technical result in part of the method is achieved due to the fact that the transmural pressure in the limb is reduced, the amplitude of plethysmographic signals is recorded at various pressures, the pressure is determined at which the amplitude of the PG signal is maximum, the pressure is reduced to a value corresponding to a given % of the maximum amplitude, an occlusion test, during which a cuff applied proximal to the located area of the limb is pressurized at least 50 mm Hg higher than the systolic pressure of the subject, and occlusion is carried out for at least 5 minutes.
The technical result is enhanced by the fact that the transmural pressure is reduced by applying a cuff in which pressure is created to the area of the limb.
The pressure on the tissue of the limb is increased discretely in increments of 5 mm Hg. and a step duration of 5-10 sec, register the amplitude of the PG signal.
To reduce the transmural pressure in the located artery, a mechanical force is used locally applied to the tissues of the limb.
To reduce the transmural pressure in the located artery, the hydrostatic pressure is reduced by raising the limb to a predetermined height relative to the level of the heart.
After choosing the value of the transmural pressure, at which the amplitude of the PG signal is 50% of the maximum increase in the PG signal, suprasystolic pressure is created in the occlusal cuff installed proximal to the located artery, and a plethysmographic signal is recorded.
After at least 5 minutes exposure of the occlusive cuff installed proximal to the located artery, the pressure in it is dropped to zero, and the registration of changes in the PG signal is carried out simultaneously in two reference and test channels for at least 3 minutes.
The registered plethysmographic signal after the occlusion test is analyzed with the simultaneous use of amplitude and temporal analysis according to the data obtained from two reference and test channels.
When carrying out amplitude analysis, the values of the signal amplitude in the reference and test channels, the rate of increase in the signal amplitude in the test channel, the ratio of the signal amplitudes of the maximum obtained at different transmural pressure values are compared with the maximum signal obtained after the occlusion test.
When performing time analysis, plethysmographic curves obtained from the reference and test channels are compared, the signal is normalized, and then the delay time or phase shift is determined.
The technical result in terms of the device is achieved due to the fact that the device includes a sensor unit, made two-channel and having the ability to register pulse curves from peripheral arteries, a pressure generating unit, made with the ability to create a stepwise pressure in the cuff, and an electronic unit, made with the ability to determine cuff pressure corresponding to the maximum amplitude of the PG signal and control of the pressure generation unit to set the pressure in the cuff corresponding to the PG signal amplitude constituting a predetermined percentage of the increase in the maximum amplitude, while the sensor unit is connected to the electronic unit, to the output of which the pressure generation unit is connected.
The technical result is enhanced by the fact that the pressure generation unit is configured to create a stepwise increasing pressure in the cuff in increments of 5 mm Hg. Art. and a step duration of 5-10 seconds.
The sensor block in each channel includes an infrared diode and a photodetector, located with the possibility of registering a light signal passing through the located area.
The sensor block in each channel includes an infrared diode and a photodetector located with the possibility of recording the scattered light signal reflected from the located area.
The sensor unit includes impedance measuring electrodes, or Hall sensors, or an elastic tube filled with an electrically conductive material.
The photodetector is connected to a filter that can extract the pulse component from the total signal.
The sensor unit includes means for maintaining the set temperature of the body area being located.
The device includes a liquid crystal display for displaying the results of an assessment of endothelial function and/or an interface connected to an electronic unit for transmitting data on endothelial function to a computer.
The technical essence of the claimed inventions and the possibility of achieving a technical result achieved as a result of their use will be more understandable when describing an embodiment with reference to the positions of the drawings, where figure 1 illustrates the dynamics of volumetric blood flow and the diameter of the brachial artery during an occlusive test, on figure 2 shows a diagram of the formation of the PPG signal, figure 3 shows the PPG curve, figure 4 shows a family of PPG curves obtained at different values of transmural pressure in patients in the control group, figure 5 shows the effect of changes in hydrostatic pressure on the amplitude of the PPG signal, and figure 6 presents a schematic block diagram of the claimed device.
The electronic unit determines the pressure in the cuff 1, corresponding to the maximum amplitude of the PG signal, and controls the pressure generation unit to set the pressure in the cuff 1, corresponding to the amplitude of the PG signal, which is a predetermined percentage (50%) of the maximum amplitude increase. It is possible to perform the sensor unit in several versions: in the first version, the infrared LED 2 and the photodetector 3 are located with the possibility of registering the light signal passing through the located area, on opposite sides of the located area of the limb, in the second, the infrared LED 2 and the photodetector 3 are located with the possibility of registering the reflected from the located area of the scattered light signal, on one side of the located vessel.
In addition, the sensor unit can be made on the basis of impedance electrodes, or Hall sensors, or an elastic tube filled with an electrically conductive material.
The endothelial function is assessed based on the registration of the PG signal obtained using a sensor unit installed on the upper limbs of the examined patient, followed by electrical conversion of the received signal during a linear increase in pressure in the cuff 1 (or the value of the locally applied force to the located artery) until the maximum amplitude of the signal, after which the pressure in the cuff or the locally applied force is fixed, and the occlusion test is performed at a fixed pressure or force. In this case, the sensor block is installed on the inner side of the cuff 1 or is located at the end of the device that creates force in the area of the projection of the artery on the skin surface. To automatically set this pressure, feedback is used on the amplitude of the PG signal coming from the digital-to-analogue converter 8 through the controller 9 to the compressor 11 of the pressure generation unit.
An occlusion test is performed using a cuff installed proximally (shoulder, forearm, wrist) relative to the located artery (brachial, radial or digital). In this case, the signal received from the other limb, on which the occlusion test is not performed, is the reference.
The claimed method for determining the state of the endothelial function of the examined patient includes two main stages: the first allows obtaining a number of plethysmographic curves recorded at different pressures in the cuff 1 (or the forces applied to the located artery), and the second stage is the occlusion test itself. The result of the first stage is information about the viscoelastic properties of the arterial bed and the choice of pressure or force for the occlusion test. Changes in the amplitude of the PG signal under the action of applied pressure or force indicate the tone of the smooth muscles of the artery and the state of its elastic components (elastin and collagen). Locally applied pressure or force is accompanied by a change in transmural pressure, the magnitude of which is determined by the difference between arterial pressure and externally applied pressure or force. With a decrease in transmural pressure, the tone of smooth muscles decreases, which is accompanied by an increase in the lumen of the artery, respectively, with an increase in transmural pressure, narrowing of the artery occurs. This is the myogenic regulation of blood flow, aimed at maintaining optimal pressure in the microcirculation system. So, when the pressure in the main vessel changes from 150 mm Hg. up to 50 mm Hg in the capillaries, the pressure remains practically unchanged.
A change in smooth muscle tone is realized not only in the form of narrowing or dilatation of the artery, but also leads, respectively, to an increase in the stiffness or compliance of the arterial wall. With a decrease in transmural pressure, the smooth muscle apparatus of the vascular wall relaxes to one degree or another, which manifests itself in PPG as an increase in signal amplitude. The maximum amplitude occurs at transmural pressure equal to zero. This is shown schematically in FIG. 4, where the S-shaped deformation curve shows that the maximum volume increment is determined at a transmural pressure close to zero. With equal pulse pressure waves applied to different parts of the deformation curve, the maximum plethysmographic signal is observed in the region close to zero transmural pressure. In patients of the control group, comparable in age and diastolic pressure with a group of people with clinical manifestations of coronary disease, the increase in signal amplitude with changes in transmural pressure can be more than 100% (figure 4). Whereas in the group of patients with coronary artery disease this increase in amplitude does not exceed 10-20%.
Such dynamics of changes in the amplitude of the PG signal at different values of transmural pressure can only be associated with the peculiarities of the viscoelastic properties of the arterial bed in healthy people and patients with stenosing atherosclerosis of various localizations. Arterial smooth muscle tone can be considered predominantly as a viscous component, while elastin and collagen fibers are a purely elastic component of the structure of the vascular wall. By reducing the smooth muscle tone when approaching zero values of transmural pressure, we kind of reduce the contribution of the viscous component of smooth muscles to the deformation curve. Such a technique allows not only to conduct a more detailed analysis of the curve of deformation of the elastic components of the arterial vascular wall, but also, in more favorable conditions, to register the phenomenon of reactive hyperemia after an occlusion test.
The increase in the diameter of the afferent artery is associated with the functioning of endothelial cells. An increase in shear stress after an occlusive test leads to an increase in the synthesis of nitric oxide (NO). A so-called "flow-induced dilation" occurs. When the function of endothelial cells is impaired, the ability to produce nitric oxide and other vasoactive compounds is reduced, which leads to the absence of the phenomenon of flow - induced vascular dilatation. In this situation, full-fledged reactive hyperemia does not occur. Currently, this phenomenon is used to detect endothelial dysfunction, i.e. endothelial dysfunction. Flow-induced dilatation of the vessel is determined by the following sequence of events: occlusion, increase in blood flow, effect of shear stress on endothelial cells, nitric oxide synthesis (as an adaptation to increased blood flow), effect of NO on smooth muscle.
The maximum amount of blood flow is reached 1-2 seconds after the removal of occlusion. It should be noted that while monitoring the amount of blood flow and the diameter of the artery initially increases the amount of blood flow, and only then changes the diameter of the vessel (figure 1). After a quick (several seconds) achievement of the maximum blood flow velocity, the diameter of the artery increases, reaching a maximum after 1 minute. Then it returns to the initial value within 2-3 minutes. Using the example of the state of the elastic modulus of the arterial wall in patients with arterial hypertension, we can make an assumption about the possible involvement of the initial stiffness of the artery in the manifestation of the response of endothelial cells to an occlusive test. It cannot be ruled out that with the same production of nitric oxide by endothelial cells, the manifestation of the response by the smooth muscle cells of the artery will be determined by the initial state of the modulus of elasticity of the arterial wall. To normalize the manifestation of the response of the smooth muscle apparatus of the arterial wall, it is desirable to have the initial stiffness of the arteries in different patients, if not identical, then as close as possible. One of the options for such a unification of the initial state of the arterial wall is the selection of the transmural pressure value, at which its greatest compliance is noted.
Evaluation of the results of an occlusive test according to the parameters of reactive hyperemia can be carried out not only on the brachial artery, but also on smaller vessels.
An optical method was used to determine the flow-dependent dilatation. The method is based on an increase in optical density associated with a pulsed increase in the blood volume of the located artery. The incoming pulse wave stretches the walls of the artery, increasing the diameter of the vessel. Since during PPG the optical sensor registers not a change in the diameter of the artery, but an increase in blood volume, which is equal to the square of the radius, this measurement can be carried out with greater accuracy. Figure 2 shows the principle of obtaining PPG signal. The photodiode registers the light flux that has passed through the located area of the finger tissue. With each pulse wave, the artery of the finger, expanding, increases the volume of blood. Blood hemoglobin largely absorbs infrared radiation, which leads to an increase in optical density. The pulse wave passing through the artery changes its diameter, which is the main component of the pulse increase in blood volume in the located area.
Figure 3 shows the PPG curve. Two peaks can be seen on the curve, the first of which is associated with the contraction of the heart, the second with the reflected pulse wave. This curve was obtained by installing an optical sensor on the last phalanx of the index finger.
Before starting measurements, the compressor 11, at the signal of the controller 9, creates pressure in the cuff 1. The increase in pressure is carried out stepwise with a step of 5 mm Hg, the duration of each step is 5-10 seconds. With increasing pressure, the transmural pressure decreases, and when the pressure in the cuff is equal to the pressure in the located artery, it becomes equal to zero. At each step, the PPG signal coming from the photodetector 3 is registered. The signal from the output of the transducer 4 is amplified in the amplifier 5 and filtered in the filter 6 to cut out noise with an industrial frequency of 50 Hz and its harmonics. The main amplification of the signal is carried out by a scalable (instrumental) amplifier 7. The amplified voltage is supplied to the analog-to-digital converter 8 and then through the USB interface 10 to the computer. The controller 9 determines the pressure at which the signal amplitude is maximum. Synchronous detection is used to improve the signal-to-noise ratio.
The procedure for assessing endothelial function is divided into two parts:
1) reduction of transmural pressure with the help of pressure applied to a part of the finger (cuff with air, elastic occluder, mechanical compression) or by changing hydrostatic pressure by raising the limb to a certain height. The latter procedure can completely replace the imposition of force from the outside on the vessel wall. In a simplified version of the endothelial state assessment, it is possible to exclude a complex automation scheme, and only by raising and lowering the hand to determine the average pressure according to the maximum amplitude of the plethysmographic signal, reach the linear section of the compliance curve (50% of the maximum increase) and then conduct an occlusive test. The only disadvantage of this approach is the need to position the hand and perform the occlusion with an elevated hand.
With a decrease in transmural pressure, the PPG pulse component increases, which corresponds to an increase in compliance of the artery under study. When exposed to a sequence of increasing pressures applied to the finger, one can, on the one hand, see the severity of the autoregulatory reaction, and on the other hand, choose the optimal conditions (according to the magnitude of the transmural pressure) for retrieving information during an occlusive test (selection of the steepest section on the curve of arterial compliance );
2) creating arterial occlusion by applying suprasystolic pressure (by 30 mm Hg) for 5 minutes. After a quick release of pressure in the cuff installed on the radial artery, the dynamics of the PPG curve is recorded (amplitude and time analysis). Registration of changes in the PG signal is carried out simultaneously on two reference and test channels for at least 3 minutes. When carrying out amplitude analysis, the values of the signal amplitude in the reference and test channels, the rate of increase in the signal amplitude in the test channel, the ratio of the amplitudes of the signals obtained maximum at different values of transmural pressure are compared with the maximum signal obtained after the occlusion test. When performing a time analysis, the plethysmographic curves obtained from the reference and test channels are compared, the signal normalization procedure is carried out, and then the delay time or phase shift is determined.
The maximum amplitudes of PPG signals were observed at zero transmural pressure (the pressure applied to the vessel from the outside is equal to the mean arterial pressure). The calculation was carried out as follows - diastolic pressure plus 1/3 pulse pressure. This arterial response to external pressure is not endothelium dependent. The choice of pressure applied from the outside to the artery not only allows a test with reactive hyperemia according to the PPG signal dynamics in the most optimal area of arterial compliance, but also has its own diagnostic value. Removal of a family of PPG curves at various values of transmural pressure makes it possible to obtain information about the rheological characteristics of the artery. This information makes it possible to distinguish between changes associated with the autoregulatory effect of the smooth muscle apparatus of the artery wall in the form of an increase in diameter from the elastic properties of the artery. An increase in the diameter of the artery leads to an increase in the constant component), due to a larger volume of blood in the scanned area. The pulse component of the signal reflects the increase in blood volume in systole. The PPG amplitude is determined by the compliance of the arterial wall during the passage of the pulse pressure wave. The lumen of the artery as such does not affect the amplitude of the PPG signal. There is no complete parallelism between the increase in the diameter of the vessel and the compliance of the wall with a change in transmural pressure.
At low transmural pressure, the arterial wall becomes less rigid compared to its mechanical properties determined at physiological blood pressure values.
Optimization of the test in terms of transmural pressure significantly increases its sensitivity, making it possible to detect pathology at the earliest stages of endothelial dysfunction. The high sensitivity of the test will make it possible to effectively evaluate the conduct of pharmacological therapy aimed at correcting endothelial dysfunction.
With an increase in pressure in the cuff to 100 mm Hg. there was a constant increase in the signal, the maximum amplitude of the signal was determined at 100 mm Hg. A further increase in cuff pressure led to a decrease in the amplitude of the PPG signal. Pressure reduction up to 75 mm Hg. was accompanied by a decrease in the PPG signal amplitude by 50%. The pressure in the cuff also changed the shape of the PPG signal (see figure 3).
The change in the shape of the PPG signal consisted in a sharp increase in the rate of rise of the systolic rise with a simultaneous delay in the moment of the beginning of the rise. These shape changes reflect the influence of the cuff on the passage of the pressure pulse wave. This phenomenon is due to the subtraction of pressure from the pulse wave, the amount of cuff pressure.
Raising the arm relative to the "point of equal pressure" (heart level) allows you to refuse to use externally applied pressure (voltage) using a cuff. Raising the arm from the "point of equal pressure" to the position extended upwards increases the PPG amplitude. Subsequent lowering of the hand to the initial level reduces the amplitude to the initial level.
Gravity is an important factor influencing the magnitude of transmural pressure. The transmural pressure in the digital artery of the raised hand is less than the pressure in the same artery, located at the level of the heart, by the product of the blood density, the acceleration of gravity and the distance from the "point of equality of pressure":
where Ptrh - transmural pressure in the digital artery of the raised hand,
Ptrho - transmural pressure in the digital artery at the level of the heart, p - blood density (1.03 g/cm), g - acceleration due to gravity (980 cm/sec), h - distance from the point of equal pressure to the digital artery of the raised hand (90 cm). At a given distance from the "point of equal pressure", the pressure of a standing person with a raised arm is 66 mm Hg. below the mean pressure in the digital artery, measured at the level of the heart.
Thus, the transmural pressure can be reduced by increasing the externally applied pressure or by decreasing the pressure in the vessel. Reducing the pressure in the digital artery is easy enough. To do this, you need to raise the brush above the level of the heart. Gradually raising the hand, we reduce the transmural pressure in the digital artery. In this case, the amplitude of the PPG signal increases sharply. In a raised hand, the average pressure in the digital artery can drop to 30 mm Hg, while when the hand is at the level of the heart, it is 90 mm Hg. Transmural pressure in the arteries of the lower leg can be four times greater than in the arteries of the raised arm. The effect of hydrostatic pressure on the value of transmural pressure can be used in a functional test to assess the viscoelastic properties of the arterial wall.
The claimed inventions have the following advantages:
1) the pressure for the occlusion test is selected individually for each patient,
2) information is provided on the viscoelastic properties of the arterial bed (according to the dependence of the PG signal amplitude on pressure (force)),
3) improved signal-to-noise ratio is provided,
4) an occlusive test is performed in the most optimal area of arterial compliance,
5) the inventions make it possible to obtain information about the rheological characteristics of the artery by taking a family of PPG curves at various values of transmural pressure,
6) inventions increase the sensitivity of the test, and consequently, the reliability of the assessment of endothelial function,
7) allow to detect pathology at the earliest stages of endothelial dysfunction,
8) allow you to reliably assess the effectiveness of ongoing pharmacotherapy.
1. A method for non-invasive determination of endothelial function, including an occlusive test, during which a pressure exceeding the systolic pressure of the subject is created in the cuff, which is applied proximally from the located area of the limb, and occlusion is carried out for 5 minutes, characterized in that at the first stage, a decrease in transmural pressure in the limb, the amplitudes of plethysmographic signals are recorded at various pressures, the pressure at which the amplitude of the plethysmographic signal is maximum is determined, then the pressure is reduced to a value corresponding to a given percentage of the maximum amplitude, at the second stage an occlusive test is performed, and a pressure exceeding systolic is created test subject's pressure by at least 50 mm Hg, then after the occlusion test, the registered plethysmographic signal is analyzed with the simultaneous use of amplitude and time analysis according to the data obtained from the reference and test channels.
2. The method according to claim 1, characterized in that the transmural pressure is reduced by applying a cuff in which pressure is created to the area of the limb.
3. The method according to claim 1, characterized in that the pressure on the tissues of the limb is increased discretely in increments of 5 mm Hg. and a step duration of 5-10 s, the amplitude of the plethysmographic signal is simultaneously recorded.
4. The method according to claim 1, characterized in that to reduce the transmural pressure in the located artery, the hydrostatic pressure is reduced by raising the limb to a predetermined height relative to the level of the heart.
5. The method according to claim 1, characterized in that after selecting the value of the transmural pressure, at which the amplitude of the plethysmographic signal is 50% of the maximum possible value, suprasystolic pressure is created in the occlusal cuff installed proximal to the located artery, the plethysmographic signal is recorded.
6. The method according to claim 5, characterized in that after at least 5 minutes exposure of the occlusive cuff installed proximal to the located artery, the pressure in it is reduced to zero, and the registration of changes in the plethysmographic signal is carried out simultaneously for two, reference and test, channels for at least 3 minutes.
7. The method according to claim 1, characterized in that when carrying out amplitude analysis, the signal amplitudes in the reference and test channels are compared, the rate of increase of the signal amplitude in the test channel, the ratio of the signal amplitudes, the maximum obtained at different transmural pressure values with the maximum signal value, obtained after the occlusion test.
8. The method according to claim 1, characterized in that during the time analysis, the plethysmographic curves obtained from the reference and test channels are compared, the signal normalization procedure is carried out, and then the delay time or phase shift is determined.
9. A device for non-invasive determination of endothelial function, including a sensor unit made as two-channel and having the ability to register pulse curves from peripheral arteries, a pressure generating unit, made with the possibility of creating a stepwise increasing pressure in the cuff, and an electronic unit, made with the possibility of determining the pressure in the cuff , corresponding to the maximum amplitude of the plethysmographic signal, and controlling the pressure generation unit to establish pressure in the cuff corresponding to the amplitude of the plethysmography signal, which is a predetermined percentage of the maximum amplitude, while the sensor unit is connected to the electronic unit, to the output of which the pressure generation unit is connected.
10. The device according to claim 9, characterized in that the pressure generation unit is configured to create a stepwise increasing pressure in the cuff with a step of 5 mm Hg and a step duration of 5-10 s.
11. The device according to claim 9, characterized in that each channel of the sensor block includes an infrared diode and a photodetector located with the possibility of registering a light signal passing through the located area.
12. The device according to claim 9, characterized in that each channel of the sensor block includes an infrared diode and a photodetector located with the possibility of recording the scattered light signal reflected from the located area.
13. The device according to claim 9, characterized in that the sensor unit includes impedance electrodes, or Hall sensors, or an elastic tube filled with an electrically conductive material.
14. The device according to claim 11, characterized in that the photodetector is connected by a filter capable of separating the pulse component from the total signal.
The invention relates to medicine and physiology and can be used for a comprehensive assessment of the level of physical performance of practically healthy persons over 6 years of age of different levels of fitness, who do not have health restrictions.
The invention relates to medicine, namely to functional diagnostics, and can be used for non-invasive determination of endothelial function
The vascular endothelium has the ability to synthesize and secrete factors that cause relaxation or contraction of vascular smooth muscles in response to various stimuli. The total mass of endothelial cells that monolayerly line blood vessels from the inside (intima) in humans approaches 500 g. The total mass, high secretory ability of endothelial cells make it possible to consider this “tissue” as a kind of endocrine organ (gland). The endothelium, distributed throughout the vascular system, is obviously designed to transfer its function directly to the smooth muscle formations of the vessels. The half-life of the hormone secreted by endotheliocytes is very short - 6-25 s (due to its rapid transition to nitrates and nitrites), but it is able to contract and relax the smooth muscles of the vessels without affecting the effector formations of other organs (intestines, bronchi, uterus) .
Relaxing factors (ERF) secreted by the vascular endothelium are unstable compounds, one of which is nitric oxide (N0). In vascular endothelial cells, NO is formed from a-arginine with the participation of the enzyme - nitric oxide synthetase.
NO is considered as some common signal transduction pathway from endothelium to vascular smooth muscle. The release of NO from the endothelium is inhibited by hemoglobin and potentiated by the enzyme dismutase.
The participation of the endothelium in the regulation of vascular tone is generally recognized. For all major arteries, the sensitivity of endotheliocytes to blood flow velocity was shown, which is expressed in the release of a factor that relaxes the smooth muscles of the vessels, leading to an increase in the lumen of these arteries. Thus, the arteries continuously adjust their lumen according to the speed of blood flow through them, which ensures the stabilization of pressure in the arteries in the physiological range of changes in blood flow values. This phenomenon is of great importance in the development of working hyperemia of organs and tissues, when there is a significant increase in blood flow, as well as with an increase in blood viscosity, which causes an increase in resistance to blood flow in the vascular network. Damage to the mechanosensitivity of vascular endotheliocytes may be one of the etiological (pathogenetic) factors in the development of obliterating endoarteritis and hypertension.
The role of smoking
It is generally accepted that nicotine and carbon monoxide affect the functions of the cardiovascular system and cause changes in metabolism, increased blood pressure, pulse rate, oxygen consumption, plasma levels of catecholamines and carboxyhemoglobin, atherogenesis, etc. All this contributes to the development and acceleration of the onset of heart diseases. - vascular system
Nicotine raises blood sugar levels, which may be why smoking promotes hunger and euphoria. After smoking each cigarette, the heart rate increases, the stroke volume decreases during physical activity of different intensity.
Smoking a large number of low-nicotine cigarettes causes the same changes as smoking fewer high-nicotine cigarettes. This is a very important fact that testifies to the illusory nature of smoking safe cigarettes.
An important role in the development of damage to the cardiovascular system when smoking is played by carbon monoxide, which is inhaled as a gas with tobacco smoke. Carbon monoxide contributes to the development of atherosclerosis, affects muscle tissue (partial or total necrosis), and heart function in patients with angina pectoris, including a negative inotropic effect on the myocardium
It is important that smokers have higher blood cholesterol levels than non-smokers, which causes coronary artery blockage.
Smoking has a significant impact on coronary heart disease (CHD), the likelihood of CAD increases with the number of cigarettes consumed; this probability also increases with the duration of smoking, but decreases in individuals who have stopped smoking.
Smoking also has an impact on the development of myocardial infarction. The risk of heart attack (including recurrent) increases with the number of cigarettes smoked per day, and in older age groups, especially those over 70, smoking cigarettes with a lower nicotine content does not reduce the risk of myocardial infarction. The effect of smoking on the development of myocardial infarction is usually associated with the occurrence of coronary atherosclerosis, resulting in ischemia of the heart muscle and subsequent necrosis of it. Both containing and not containing nicotine cigarettes increase the presence of carbon monoxide in the blood, reduce the absorption of oxygen by the heart muscle.
Smoking has a significant impact on peripheral vascular disease, in particular on the development of endarteritis of the lower extremities (intermittent claudication or endarteritis obliterans), especially in diabetes mellitus. After smoking one cigarette, the spasm of peripheral vessels lasts for about 20 minutes, and therefore there is a high risk of developing obliterating endarteritis.
Smokers with diabetes are at a greater risk (by 50%) of developing obstructive peripheral vascular disease than non-smokers.
Smoking is also a risk factor in the development of atherosclerotic aortic aneurysm, which develops in smokers 8 times more often than non-smokers. Smokers have a 2-3 times increased mortality from abdominal aortic aneurysms.
Spasm of peripheral vessels, arising under the influence of nicotine, plays a role in the development of hypertension (during smoking, blood pressure rises especially strongly).
Arterial hypertension (essential hypertension). Pathogenesis. Risk factors.
Arterial hypertension- persistent increase in blood pressure. By origin, primary and secondary arterial hypertension is distinguished. A secondary increase in blood pressure is only a symptom (symptomatic hypertension), a consequence of some other disease (glomerulonephritis, narrowing of the aortic arch, pituitary adenoma or adrenal cortex, etc.).
Primary hypertension is still called essential hypertension, which indicates that its origin is unclear.
Hypertension is one of the variants of primary arterial hypertension. In primary hypertension, an increase in blood pressure is the main manifestation of the disease.
Primary hypertension accounts for 80% of all cases of arterial hypertension. The remaining 20% are secondary arterial hypertension, of which 14% are associated with diseases of the kidney parenchyma or its vessels.
Etiology. The causes of primary hypertension may be different and many of them are still not fully established. However, there is no doubt that overstrain of higher nervous activity under the influence of emotional influences has a certain significance in the occurrence of hypertension. This is evidenced by frequent cases of the development of primary hypertension in people who survived the Leningrad blockade, as well as in people of "stressful" professions. Of particular importance in this case are negative emotions, in particular, emotions that are not reacted in a motor act, when the entire force of their pathogenic effect falls on the circulatory system. On this basis, G. F. Lang called hypertension "a disease of unreacted emotions."
Arterial hypertension is "a disease of the autumn of a person's life, which deprives him of the opportunity to live until winter" (A. A. Bogomolets). This emphasizes the role of age in the origin of hypertension. However, at a young age, primary hypertension is not so rare. It is important to note that before the age of 40, men get sick more often than women, and after 40, the ratio becomes opposite.
A certain role in the occurrence of primary hypertension is played by a hereditary factor. In some families, the disease occurs several times more often than in the rest of the population. The influence of genetic factors is also evidenced by the high concordance for hypertension in identical twins, as well as the existence of rat strains predisposed or resistant to certain forms of hypertension.
Recently, in connection with epidemiological observations carried out in some countries and among nationalities (Japan, China, the Negro population of the Bahamas, some areas of the Transcarpathian region), a close relationship has been established between the level of blood pressure and the amount of salt consumed. It is believed that long-term consumption of more than 5 g of salt per day contributes to the development of primary hypertension in people who have a hereditary predisposition to it.
Successful experimental modeling of "salt hypertension" confirms the importance of excess salt intake. These observations are in good agreement with clinical data on the beneficial therapeutic effect of a low-salt diet in some forms of primary hypertension.
Thus, several etiological factors of hypertension have now been established. It is only unclear which of them is the cause, and which plays the role of the condition in the occurrence of the disease.
Precapillary and postcapillary types of hypertension of the pulmonary circulation. Causes. Consequences.
Pulmonary hypertension (BP over 20/8 mmHg) is either precapillary or postcapillary.
Precapillary form pulmonary hypertension characterized by an increase in pressure (and hence resistance) in the small arterial vessels of the pulmonary trunk system. The causes of the precapillary form of hypertension are spasm of arterioles and embolism of the branches of the pulmonary artery.
Possible causes of spasm of arterioles:
stress, emotional stress;
inhalation of cold air;
the von Euler-Liljestrand reflex (a constrictor reaction of the pulmonary vessels that occurs in response to a decrease in pO2 in the alveolar air);
hypoxia.
Possible causes of embolism of the branches of the pulmonary artery:
thrombophlebitis;
heart rhythm disturbances;
blood hypercoagulability;
polycythemia.
A sharp rise in blood pressure in the pulmonary trunk irritates baroreceptors and, by triggering the Shvachka-Parin reflex, leads to a decrease in systemic blood pressure, a slowdown in the heart rate, an increase in the blood supply to the spleen, skeletal muscles, a decrease in venous return of blood to the heart, and prevention of pulmonary edema. This further disrupts the work of the heart, up to its stop and death of the body.
Pulmonary hypertension is exacerbated by the following conditions:
decrease in air temperature;
activation of the SAS;
polycythemia;
increased blood viscosity;
coughing fits or chronic cough.
Postcapillary form of pulmonary hypertension It is caused by a decrease in the outflow of blood through the pulmonary vein system. It is characterized by congestion in the lungs, arising and aggravated by compression of the pulmonary veins by a tumor, connective tissue scars, as well as in various diseases accompanied by left ventricular heart failure (mitral stenosis, hypertension, myocardial infarction, cardiosclerosis, etc.).
It should be noted that the post-capillary form can complicate the pre-capillary form, and the pre-capillary form can complicate the post-capillary form.
Violation of the outflow of blood from the pulmonary veins (with an increase in pressure in them) leads to the inclusion of the Kitaev reflex, leading to an increase in precapillary resistance (due to narrowing of the pulmonary arteries) in the pulmonary circulation, designed to unload the latter.
Pulmonary hypotension develops with hypovolemia caused by blood loss, collapse, shock, heart defects (with blood shunting from right to left). The latter, for example, occurs in Fallot's tetrad, when a significant part of the venous low-oxygenated blood enters the arteries of the large circle, bypassing the pulmonary vessels, including bypassing the exchange capillaries of the lungs. This leads to the development of chronic hypoxia and secondary respiratory disorders.
Under these conditions, accompanied by shunting of the pulmonary blood flow, oxygen inhalation does not improve the process of blood oxygenation, hypoxemia persists. Thus, this functional test is a simple and reliable diagnostic test for this type of pulmonary blood flow disorder.
symptomatic hypertension. Species, pathogenesis. experimental hypertension.
Catad_tema Arterial hypertension - articles
Endothelial dysfunction as a new concept for the prevention and treatment of cardiovascular diseases
The end of the 20th century was marked not only by the intensive development of fundamental concepts of the pathogenesis of arterial hypertension (AH), but also by a critical revision of many ideas about the causes, mechanisms of development and treatment of this disease.
At present, AH is considered as the most complex complex of neurohumoral, hemodynamic and metabolic factors, the relationship of which is transformed over time, which determines not only the possibility of transition from one variant of the course of AH to another in the same patient, but also the deliberate simplification of ideas about the monotherapeutic approach. , and even the use of at least two drugs with a specific mechanism of action.
Page's so-called "mosaic" theory, being a reflection of the established traditional conceptual approach to the study of AH, which based AH on particular violations of the mechanisms of BP regulation, may partly be an argument against the use of a single antihypertensive agent for the treatment of AH. At the same time, such an important fact is rarely taken into account that in its stable phase, hypertension occurs with normal or even reduced activity of most systems that regulate blood pressure.
Currently, serious attention in the views on hypertension has been given to metabolic factors, the number of which, however, increases with the accumulation of knowledge and the possibilities of laboratory diagnostics (glucose, lipoproteins, C-reactive protein, tissue plasminogen activator, insulin, homocysteine, and others).
The possibilities of 24-hour BP monitoring, the peak of which was introduced into clinical practice in the 1980s, showed a significant pathological contribution of impaired 24-hour BP variability and features of circadian BP rhythms, in particular, a pronounced pre-morning rise, high circadian BP gradients, and the absence of a nocturnal BP decrease, which largely associated with fluctuations in vascular tone.
Nevertheless, by the beginning of the new century, a direction clearly crystallized, which largely included the accumulated experience of fundamental research, on the one hand, and focused the attention of clinicians on a new object - endothelium - as a target organ of AH, the first to come into contact with biologically active substances and most early damaged in hypertension.
On the other hand, the endothelium implements many links in the pathogenesis of hypertension, directly participating in the increase in blood pressure.
The role of the endothelium in cardiovascular pathology
In the form familiar to the human mind, the endothelium is an organ weighing 1.5-1.8 kg (comparable to the weight, for example, of the liver) or a continuous monolayer of endothelial cells 7 km long, or occupying the area of a football field or six tennis courts. Without these spatial analogies, it would be difficult to imagine that a thin semi-permeable membrane that separates the blood flow from the deep structures of the vessel continuously produces a huge amount of the most important biologically active substances, thus being a giant paracrine organ distributed throughout the entire territory of the human body.
The barrier role of the vascular endothelium as an active organ determines its main role in the human body: maintaining homeostasis by regulating the equilibrium state of opposite processes - a) vascular tone (vasodilation/vasoconstriction); b) anatomical structure of vessels (synthesis/inhibition of proliferation factors); c) hemostasis (synthesis and inhibition of factors of fibrinolysis and platelet aggregation); d) local inflammation (production of pro- and anti-inflammatory factors).
It should be noted that each of the four functions of the endothelium, which determines the thrombogenicity of the vascular wall, inflammatory changes, vasoreactivity and stability of an atherosclerotic plaque, is directly or indirectly associated with the development and progression of atherosclerosis, hypertension and its complications. Indeed, recent studies have shown that plaque tears leading to myocardial infarction do not always occur in the zone of maximum coronary artery stenosis, on the contrary, they often occur in places of small narrowing - less than 50% according to angiography.
Thus, the study of the role of the endothelium in the pathogenesis of cardiovascular diseases (CVD) led to the understanding that the endothelium regulates not only peripheral blood flow, but also other important functions. That is why the concept of the endothelium as a target for the prevention and treatment of pathological processes leading to or implementing CVD has become unifying.
Understanding the multifaceted role of the endothelium, already at a qualitatively new level, again leads to the well-known, but well-forgotten formula "human health is determined by the health of its blood vessels."
In fact, by the end of the 20th century, namely in 1998, after receiving the Nobel Prize in medicine, F. Murad, Robert Furschgot and Luis Ignarro, a theoretical basis was formed for a new direction of fundamental and clinical research in the field of hypertension and other CVD - the development participation of the endothelium in the pathogenesis of hypertension and other CVD, as well as ways to effectively correct its dysfunction.
It is believed that drug or non-drug intervention in the early stages (pre-illness or early stages of the disease) can delay its onset or prevent progression and complications. The leading concept of preventive cardiology is based on the assessment and correction of so-called cardiovascular risk factors. The unifying principle for all such factors is that sooner or later, directly or indirectly, they all cause damage to the vascular wall, and above all, in its endothelial layer.
Therefore, it can be assumed that at the same time they are also risk factors for endothelial dysfunction (DE) as the earliest phase of damage to the vascular wall, atherosclerosis and hypertension, in particular.
DE is, first of all, an imbalance between the production of vasodilating, angioprotective, antiproliferative factors on the one hand (NO, prostacyclin, tissue plasminogen activator, C-type natriuretic peptide, endothelial hyperpolarizing factor) and vasoconstrictive, prothrombotic, proliferative factors, on the other hand ( endothelin, superoxide anion, thromboxane A2, tissue plasminogen activator inhibitor). At the same time, the mechanism of their final implementation is unclear.
One thing is obvious - sooner or later, cardiovascular risk factors upset the delicate balance between the most important functions of the endothelium, which ultimately results in the progression of atherosclerosis and cardiovascular incidents. Therefore, the thesis of the need to correct endothelial dysfunction (i.e., normalize endothelial function) as an indicator of the adequacy of antihypertensive therapy became the basis of one of the new clinical directions. The evolution of the tasks of antihypertensive therapy was concretized not only to the need to normalize the level of blood pressure, but also to normalize the function of the endothelium. In fact, this means that lowering blood pressure without correcting endothelial dysfunction (DE) cannot be considered a successfully solved clinical problem.
This conclusion is fundamental, also because the main risk factors for atherosclerosis, such as hypercholesterolemia, hypertension, diabetes mellitus, smoking, hyperhomocysteinemia, are accompanied by a violation of endothelium-dependent vasodilation - both in the coronary and peripheral circulation. And although the contribution of each of these factors to the development of atherosclerosis has not been fully determined, this does not change the prevailing ideas.
Among the abundance of biologically active substances produced by the endothelium, the most important is nitric oxide - NO. The discovery of the key role of NO in cardiovascular homeostasis was awarded the Nobel Prize in 1998. Today it is the most studied molecule involved in the pathogenesis of AH and CVD in general. Suffice it to say that the disturbed relationship between angiotensin II and NO is quite capable of determining the development of hypertension.
Normally functioning endothelium is characterized by continuous basal NO production by endothelial NO synthetase (eNOS) from L-arginine. This is necessary to maintain normal basal vascular tone. At the same time, NO has angioprotective properties, inhibiting the proliferation of vascular smooth muscle and monocytes, and thereby preventing the pathological restructuring of the vascular wall (remodeling), the progression of atherosclerosis.
NO has an antioxidant effect, inhibits platelet aggregation and adhesion, endothelial-leukocyte interactions, and monocyte migration. Thus, NO is a universal key angioprotective factor.
In chronic CVD, as a rule, there is a decrease in NO synthesis. There are quite a few reasons for this. To summarize, it is obvious that a decrease in NO synthesis is usually associated with impaired expression or transcription of eNOS, including metabolic origin, a decrease in the availability of L-arginine stores for endothelial NOS, accelerated NO metabolism (with increased formation of free radicals), or a combination of both.
Despite the versatility of NO effects, Dzau et Gibbons managed to schematically formulate the main clinical consequences of chronic NO deficiency in the vascular endothelium, thereby showing the real consequences of DE in the model of coronary heart disease and drawing attention to the exceptional importance of its correction at the earliest possible stages.
An important conclusion follows from Scheme 1: NO plays a key angioprotective role even in the early stages of atherosclerosis.
Scheme 1. MECHANISMS OF ENDOTHELIAL DYSFUNCTION
FOR CARDIOVASCULAR DISEASES
Thus, it has been proven that NO reduces the adhesion of leukocytes to the endothelium, inhibits the transendothelial migration of monocytes, maintains normal endothelial permeability for lipoproteins and monocytes, and inhibits LDL oxidation in the subendothelium. NO is able to inhibit the proliferation and migration of vascular smooth muscle cells, as well as their collagen synthesis. The administration of NOS inhibitors after vascular balloon angioplasty or under conditions of hypercholesterolemia led to intimal hyperplasia, and, conversely, the use of L-arginine or NO donors reduced the severity of induced hyperplasia.
NO has antithrombotic properties, inhibiting platelet adhesion, activation and aggregation, activating tissue plasminogen activator. There is strong evidence to suggest that NO is an important factor modulating the thrombotic response to plaque rupture.
And of course, NO is a powerful vasodilator that modulates vascular tone, leading to vasorelaxation indirectly through an increase in cGMP levels, maintaining basal vascular tone and performing vasodilation in response to various stimuli - blood shear stress, acetylcholine, serotonin.
Impaired NO - dependent vasodilation and paradoxical vasoconstriction of epicardial vessels is of particular clinical importance for the development of myocardial ischemia under conditions of mental and physical stress, or cold stress. And given that myocardial perfusion is regulated by resistive coronary arteries, the tone of which depends on the vasodilator capacity of the coronary endothelium, even in the absence of atherosclerotic plaques, NO deficiency in the coronary endothelium can lead to myocardial ischemia.
Assessment of endothelial function
The decrease in NO synthesis is the main factor in the development of DE. Therefore, it would seem that nothing is simpler than measuring NO as a marker of endothelial function. However, the instability and short lifetime of the molecule severely limit the application of this approach. The study of stable NO metabolites in plasma or urine (nitrates and nitrites) cannot be routinely used in the clinic due to the extremely high requirements for preparing the patient for the study.
In addition, the study of nitric oxide metabolites alone is unlikely to provide valuable information on the state of nitrate-producing systems. Therefore, if it is impossible to simultaneously study the activity of NO synthetases, along with a carefully controlled process of patient preparation, the most realistic way to assess the state of the endothelium in vivo is to study endothelium-dependent vasodilation of the brachial artery using acetylcholine or serotonin infusion, or using veno-occlusive plethysmography, as well as with the help of the latest techniques - samples with reactive hyperemia and the use of high-resolution ultrasound.
In addition to these methods, several substances are considered as potential markers of DE, the production of which can reflect the function of the endothelium: tissue plasminogen activator and its inhibitor, thrombomodulin, von Willebrand factor.
Therapeutic strategies
Evaluation of DE as a violation of endothelium-dependent vasodilation due to a decrease in NO synthesis, in turn, requires a revision of therapeutic strategies for influencing the endothelium in order to prevent or reduce damage to the vascular wall.
It has already been shown that improvement in endothelial function precedes the regression of structural atherosclerotic changes. Influencing bad habits - smoking cessation - leads to an improvement in endothelial function. Fatty food contributes to the deterioration of endothelial function in apparently healthy individuals. The intake of antioxidants (vitamin E, C) contributes to the correction of endothelial function and inhibits the thickening of the intima of the carotid artery. Physical activity improves the condition of the endothelium even in heart failure.
Improved glycemic control in patients with diabetes mellitus is in itself a factor in the correction of DE, and normalization of the lipid profile in patients with hypercholesterolemia led to the normalization of endothelial function, which significantly reduced the incidence of acute cardiovascular incidents.
At the same time, such a "specific" effect aimed at improving the synthesis of NO in patients with coronary artery disease or hypercholesterolemia, such as replacement therapy with L-arginine, a NOS substrate - synthetase, also leads to the correction of DE. Similar data were obtained with the use of the most important cofactor of NO-synthetase - tetrahydrobiopterin - in patients with hypercholesterolemia.
In order to reduce NO degradation, the use of vitamin C as an antioxidant also improved endothelial function in patients with hypercholesterolemia, diabetes mellitus, smoking, arterial hypertension, coronary artery disease. These data indicate a real possibility of influencing the NO synthesis system, regardless of the reasons that caused its deficiency.
Currently, almost all groups of drugs are being tested for their activity in relation to the NO synthesis system. An indirect effect on DE in coronary artery disease has already been shown for ACE inhibitors that improve endothelial function indirectly through an indirect increase in NO synthesis and a decrease in NO degradation.
Positive effects on the endothelium have also been obtained in clinical trials of calcium antagonists, however, the mechanism of this effect is unclear.
A new direction in the development of pharmaceuticals, apparently, should be considered the creation of a special class of effective drugs that directly regulate the synthesis of endothelial NO and thereby directly improve the function of the endothelium.
In conclusion, we would like to emphasize that disturbances in vascular tone and cardiovascular remodeling lead to damage to target organs and complications of hypertension. It becomes obvious that biologically active substances that regulate vascular tone simultaneously modulate a number of important cellular processes, such as proliferation and growth of vascular smooth muscle, growth of mesanginal structures, the state of the extracellular matrix, thereby determining the rate of progression of hypertension and its complications. Endothelial dysfunction, as the earliest phase of vessel damage, is primarily associated with a deficiency in NO synthesis, the most important factor-regulator of vascular tone, but an even more important factor on which structural changes in the vascular wall depend.
Therefore, the correction of DE in AH and atherosclerosis should be a routine and mandatory part of therapeutic and preventive programs, as well as a strict criterion for evaluating their effectiveness.
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Earlier, we noted that the endothelium of the vascular wall has a significant effect on the composition of the blood. It is known that the diameter of the average capillary is 6-10 µm, its length is about 750 µm. The total cross section of the vascular bed is 700 times the diameter of the aorta. The total area of the network of capillaries is 1000 m 2 . If we take into account that pre- and post-capillary vessels are involved in the exchange, this value doubles. There are dozens, and most likely hundreds of biochemical processes associated with intercellular metabolism: its organization, regulation, implementation. According to modern concepts, the endothelium is an active endocrine organ, the largest in the body and diffusely scattered throughout all tissues. The endothelium synthesizes compounds important for blood coagulation and fibrinolysis, adhesion and platelet aggregation. It is a regulator of the activity of the heart, vascular tone, blood pressure, filtration function of the kidneys and metabolic activity of the brain. It controls the diffusion of water, ions, metabolic products. The endothelium responds to the mechanical pressure of the blood (hydrostatic pressure). Given the endocrine functions of the endothelium, the British pharmacologist, Nobel Prize winner John Wayne called the endothelium the “maestro of blood circulation”.
The endothelium synthesizes and secretes a large number of biologically active compounds that are released according to the current need. The functions of the endothelium are determined by the presence of the following factors:
1. controlling the contraction and relaxation of the muscles of the vascular wall, which determines its tone;
2. participating in the regulation of the liquid state of the blood and contributing to thrombosis;
3. controlling the growth of vascular cells, their repair and replacement;
4. participating in the immune response;
5. Participating in the synthesis of cytomedines or cellular mediators that ensure the normal activity of the vascular wall.
Nitric oxide. One of the most important molecules produced by the endothelium is nitric oxide, the final substance that performs many regulatory functions. The synthesis of nitric oxide is carried out from L-arginine by the constitutive enzyme NO-synthase. To date, three isoforms of NO synthases have been identified, each of which is a product of a separate gene, encoded and identified in different cell types. Endothelial cells and cardiomyocytes have a so-called NO synthase 3 (ecNOs or NOs3)
Nitric oxide is present in all types of endothelium. Even at rest, the endotheliocyte synthesizes a certain amount of NO, maintaining the basal vascular tone.
With contraction of the muscular elements of the vessel, a decrease in the partial tension of oxygen in the tissue in response to an increase in the concentration of acetylcholine, histamine, noradrenaline, bradykinin, ATP, etc., the synthesis and secretion of NO by the endothelium increases. The production of nitric oxide in the endothelium also depends on the concentration of calmodulin and Ca 2+ ions.
The function of NO is reduced to inhibition of the contractile apparatus of smooth muscle elements. In this case, the enzyme guanylate cyclase is activated and an intermediary (messenger) is formed - cyclic 3 / 5 / -guanosine monophosphate.
It has been established that the incubation of endothelial cells in the presence of one of the proinflammatory cytokines, TNFa, leads to a decrease in the viability of endothelial cells. But if the formation of nitric oxide increases, then this reaction protects endothelial cells from the action of TNFa. At the same time, the inhibitor of adenylate cyclase 2/5/-dideoxyadenosine completely suppresses the cytoprotective effect of the NO donor. Therefore, one of the pathways of NO action may be cGMP-dependent inhibition of cAMP degradation.
What does NO do?
Nitric oxide inhibits adhesion and aggregation of platelets and leukocytes, which is associated with the formation of prostacyclin. At the same time, it inhibits the synthesis of thromboxane A 2 (TxA 2). Nitric oxide inhibits the activity of angiotensin II, which causes an increase in vascular tone.
NO regulates local growth of endothelial cells. Being a free radical compound with a high reactivity, NO stimulates the toxic effect of macrophages on tumor cells, bacteria, and fungi. Nitric oxide counteracts oxidative damage to cells, probably due to the regulation of intracellular glutathione synthesis mechanisms.
With the weakening of NO generation, the occurrence of hypertension, hypercholesterolemia, atherosclerosis, as well as spastic reactions of the coronary vessels is associated. In addition, disruption of nitric oxide generation leads to endothelial dysfunction regarding the formation of biologically active compounds.
Endothelin. One of the most active peptides secreted by the endothelium is the vasoconstrictor factor endothelin, whose action is manifested in extremely small doses (one millionth of a mg). There are 3 isoforms of endothelin in the body, which differ very little in their chemical composition from each other, include 21 amino acid residues each, and differ significantly in their mechanism of action. Each endothelin is the product of a separate gene.
Endothelin 1 - the only one from this family, which is formed not only in the endothelium, but also in smooth muscle cells, as well as in neurons and astrocytes of the brain and spinal cord, mesangial cells of the kidney, endometrium, hepatocytes and epithelial cells of the mammary gland. The main stimuli for the formation of endothelin 1 are hypoxia, ischemia, and acute stress. Up to 75% of endothelin 1 is secreted by endothelial cells towards the smooth muscle cells of the vascular wall. In this case, endothelin binds to receptors on their membrane, which ultimately leads to their constriction.
Endothelin 2 - the main place of its formation are the kidneys and intestines. In small quantities, it is found in the uterus, placenta and myocardium. It practically does not differ from endothelin 1 in its properties.
Endothelin 3 constantly circulates in the blood, but its source of formation is not known. It is found in high concentrations in the brain, where it is thought to regulate functions such as the proliferation and differentiation of neurons and astrocytes. In addition, it is found in the gastrointestinal tract, lungs and kidneys.
Taking into account the functions of endothelins, as well as their regulatory role in intercellular interactions, many authors believe that these peptide molecules should be classified as cytokines.
Synthesis of endothelin is stimulated by thrombin, adrenaline, angiotensin, interleukin-I (IL-1) and various growth factors. In most cases, endothelin is secreted from the endothelium inward, to muscle cells, where receptors sensitive to it are located. There are three types of endothelin receptors: A, B and C. All of them are located on the cell membranes of various organs and tissues. Endothelial receptors are glycoproteins. Most of the synthesized endothelin interacts with EtA receptors, while a smaller part interacts with EtV-type receptors. The action of endothelin 3 is mediated through EtS receptors. At the same time, they are able to stimulate the synthesis of nitric oxide. Consequently, with the help of the same factor, 2 opposite vascular reactions are regulated - contraction and relaxation, realized by different mechanisms. However, it should be noted that under natural conditions, when the concentration of endothelins slowly accumulates, a vasoconstrictor effect is observed due to contraction of vascular smooth muscles.
Endothelin is certainly involved in coronary heart disease, acute myocardial infarction, cardiac arrhythmias, atherosclerotic vascular damage, pulmonary and cardiac hypertension, ischemic brain damage, diabetes and other pathological processes.
Thrombogenic and thrombogenic properties of the endothelium. The endothelium plays an extremely important role in keeping the blood fluid. Damage to the endothelium inevitably leads to adhesion (sticking) of platelets and leukocytes, due to which white (consisting of platelets and leukocytes) or red (including red blood cells) thrombi are formed. In connection with the above, we can assume that the endocrine function of the endothelium is reduced, on the one hand, to maintaining the liquid state of the blood, and on the other hand, to the synthesis and release of factors that can lead to stop bleeding.
Factors that contribute to stopping bleeding should include a complex of compounds that lead to adhesion and aggregation of platelets, the formation and preservation of a fibrin clot. The compounds that ensure the liquid state of the blood include inhibitors of platelet aggregation and adhesion, natural anticoagulants and factors leading to the dissolution of the fibrin clot. Let us dwell on the characteristics of the listed compounds.
It is known that thromboxane A 2 (TxA 2), von Willebrand factor (vWF), platelet activating factor (PAF), adenosine diphosphoric acid (ADP) are among the substances that induce platelet adhesion and aggregation and are formed by the endothelium.
TxA 2, mainly synthesized in the platelets themselves, however, this compound can also be formed from arachidonic acid, which is part of endothelial cells. The action of TxA 2 is manifested in case of damage to the endothelium, due to which irreversible platelet aggregation occurs. It should be noted that TxA 2 has a rather strong vasoconstrictive effect and plays an important role in the occurrence of coronary spasm.
vWF is synthesized by intact endothelium and is required for both platelet adhesion and aggregation. Various vessels are capable of synthesizing this factor to varying degrees. A high level of vWF transfer RNA was found in the endothelium of the vessels of the lungs, heart, and skeletal muscles, while its concentration in the liver and kidneys is relatively low.
PAF is produced by many cells, including endotheliocytes. This compound promotes the expression of the main integrins involved in the processes of platelet adhesion and aggregation. PAF has a wide spectrum of action and plays an important role in the regulation of the physiological functions of the body, as well as in the pathogenesis of many pathological conditions.
One of the compounds involved in platelet aggregation is ADP. When the endothelium is damaged, mainly adenosine triphosphate (ATP) is released, which, under the action of cellular ATPase, quickly turns into ADP. The latter triggers the process of platelet aggregation, which is reversible in the early stages.
The action of compounds that promote platelet adhesion and aggregation is opposed by factors that inhibit these processes. They are primarily prostacyclin or prostaglandin I 2 (PgI 2). The synthesis of prostacyclin by intact endothelium occurs constantly, but its release is observed only in the case of the action of stimulating agents. PgI 2 inhibits platelet aggregation through the formation of cAMP. In addition, nitric oxide (see above) and ecto-ADPase, which cleaves ADP to adenosine, which serves as an aggregation inhibitor, are inhibitors of platelet adhesion and aggregation.
Factors contributing to blood clotting. This should include tissue factor, which under the influence of various agonists (IL-1, IL-6, TNFa, adrenaline, lipopolysaccharide (LPS) of gram-negative bacteria, hypoxia, blood loss) is intensively synthesized by endothelial cells and enters the bloodstream. Tissue factor (FIII) triggers the so-called extrinsic pathway of blood coagulation. Under normal conditions, tissue factor is not formed by endothelial cells. However, any stressful situations, muscle activity, the development of inflammatory and infectious diseases lead to its formation and stimulation of the blood coagulation process.
TO factors that prevent blood clotting relate natural anticoagulants. It should be noted that the surface of the endothelium is covered with a complex of glycosaminoglycans with anticoagulant activity. These include heparan sulfate, dermatan sulfate, capable of binding to antithrombin III, as well as increasing the activity of heparin cofactor II and thereby increasing the antithrombogenic potential.
Endothelial cells synthesize and secrete 2 extrinsic pathway inhibitors (TFPI-1 And TFPI-2), blocking the formation of prothrombinase. TFPI-1 is able to bind factors VIIa and Xa on the surface of tissue factor. TFPI-2, being an inhibitor of serine proteases, neutralizes coagulation factors involved in the external and internal pathways of prothrombinase formation. At the same time, it is a weaker anticoagulant than TFPI-1.
Endothelial cells synthesize antithrombin III (A-III), which, when interacting with heparin, neutralizes thrombin, factors Xa, IXa, kallikrein, etc.
Finally, natural anticoagulants synthesized by the endothelium include thrombomodulin-protein C (PtC) system, which also includes protein S (PtS). This complex of natural anticoagulants neutralizes factors Va and VIIIa.
Factors affecting the fibrinolytic activity of the blood. The endothelium contains a complex of compounds that promote and prevent the dissolution of the fibrin clot. First of all, you should point out tissue plasminogen activator (TPA, TPA) is the main factor that converts plasminogen into plasmin. In addition, the endothelium synthesizes and secretes the urokinase plasminogen activator. It is known that the latter compound is also synthesized in the kidneys and excreted in the urine.
At the same time, endothelium synthesizes and inhibitors of tissue plasminogen activator (ITAP, ITPA) I, II and III types. All of them differ in their molecular weight and biological activity. The most studied of them is type I ITAP. It is constantly synthesized and secreted by endotheliocytes. Other ITAPs play a less prominent role in the regulation of blood fibrinolytic activity.
It should be noted that under physiological conditions the action of fibrinolysis activators prevails over the influence of inhibitors. Under stress, hypoxia, physical activity, along with the acceleration of blood clotting, activation of fibrinolysis is noted, which is associated with the release of TPA from endothelial cells. Meanwhile, tPA inhibitors are found in excess in endotheliocytes. Their concentration and activity predominate over the action of tPA, although the intake into the bloodstream under natural conditions is significantly limited. With the depletion of TPA reserves, which is observed with the development of inflammatory, infectious and oncological diseases, with the pathology of the cardiovascular system, with normal and especially pathological pregnancy, as well as with genetically determined insufficiency, the action of ITAP begins to predominate, due to which, along with the acceleration of blood coagulation inhibition of fibrinolysis develops.
Factors regulating the growth and development of the vascular wall. It is known that the endothelium synthesizes vascular growth factor. At the same time, the endothelium contains a compound that inhibits angiogenesis.
One of the main factors of angiogenesis is the so-called vascular endothelial growth factor or VGEF(from the words vascular growth endothelial cell factor), which has the ability to induce chemotaxis and mitogenesis of ECs and monocytes and plays an important role not only in neoangiogenesis, but also in vasculogenesis (early formation of blood vessels in the fetus). Under its influence, the development of collaterals is enhanced and the integrity of the endothelial layer is maintained.
Fibroblast growth factor (FGF) is related not only to the development and growth of fibroblasts, but also participates in the control of the tone of smooth muscle elements.
One of the main inhibitors of angiogenesis affecting the adhesion, growth and development of endothelial cells is thrombospondin. It is a cellular matrix glycoprotein synthesized by various cell types, including endothelial cells. Synthesis of thrombospondin is controlled by the P53 oncogene.
Factors involved in immunity. Endothelial cells are known to play an extremely important role in both cellular and humoral immunity. It has been established that endotheliocytes are antigen-presenting cells (APC), that is, they are able to process antigen (Ag) into an immunogenic form and "present" it to T- and B-lymphocytes. The surface of endothelial cells contains both HLA classes I and II, which is a necessary condition for antigen presentation. From the vascular wall and, in particular, from the endothelium, a complex of polypeptides was isolated that enhances the expression of receptors on T- and B-lymphocytes. At the same time, endothelial cells are able to produce a number of cytokines that contribute to the development of the inflammatory process. Such compounds include IL-1 a and b, TNFa, IL-6, a- and b-chemokines and others. In addition, endothelial cells secrete growth factors that affect hematopoiesis. These include granulocyte colony stimulating factor (G-CSF, G-CSF), macrophage colony stimulating factor (M-CSF, M-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF, G-MSSF) and others. Recently, a compound of a polypeptide nature has been isolated from the vascular wall, which sharply enhances the processes of erythropoiesis and contributes in the experiment to the elimination of hemolytic anemia caused by the introduction of carbon tetrachloride.
Cytomedins. Vascular endothelium, like other cells and tissues, is a source of cellular mediators - cytomedins. Under the influence of these compounds, which are a complex of polypeptides with a molecular weight of 300 to 10,000 D, the contractile activity of the smooth muscle elements of the vascular wall is normalized, so that blood pressure remains within normal limits. Cytomedins from vessels promote the processes of regeneration and repair of tissues and, possibly, ensure the growth of vessels when they are damaged.
Numerous studies have established that all biologically active compounds synthesized by the endothelium or arising in the process of partial proteolysis, under certain conditions, are able to enter the vascular bed and thus affect the composition and functions of the blood.
Of course, we have presented a far from complete list of factors synthesized and secreted by the endothelium. However, these data are sufficient to conclude that the endothelium is a powerful endocrine network that regulates numerous physiological functions.
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The endothelium and its basement membrane act as a histohematic barrier, separating blood from the intercellular environment of surrounding tissues. At the same time, endothelial cells are connected to each other by dense and slit-like connective complexes. Along with the barrier function, the endothelium provides the exchange of various substances between the blood and surrounding tissues. The exchange process at the level of capillaries is carried out with the help of pinocytosis, as well as the diffusion of substances through the finestra and pores. Endotelocytes supply basement membrane components to the subendothelial layer: collagen, elastin, laminin, proteases, as well as their inhibitors: thrombospondin, mucopolysaccharides, vigronectin, fibronectin, von Willebrand factor and other proteins that are of great importance for intercellular interaction and the formation of a diffuse barrier that prevents entry of blood into the extravascular space. The same mechanism allows the endothelium to regulate the penetration of biologically active molecules into the underlying smooth muscle layer.
Thus, the endothelial lining can be traversed in three highly regulated ways. First, some molecules can reach smooth muscle cells by penetrating junctions between endothelial cells. Secondly, molecules can be transported across endothelial cells by vesicles (the process of pinocytosis). Finally, lipid-soluble molecules can move within the lipid bilayer.
Endothelial cells of the coronary vessels, in addition to the barrier function, are endowed with the ability to control vascular tone (motor activity of the smooth muscles of the vascular wall), adhesive properties of the inner surface of the vessels, as well as metabolic processes in the myocardium. These and other functional capabilities of endotheliocytes are determined by their sufficiently high ability to produce various biologically active molecules, including cytokines, anti- and procoagulants, anti-mitogens, etc., from the lumen of the vessel to the subintimal layers of its wall;
The endothelium is able to produce and secrete a number of substances that have both vasoconstrictive and vasodilating effects. With the participation of these substances, self-regulation of vascular tone occurs, which significantly complements the function of vascular neuroregulation.
Intact vascular endothelium synthesizes vasodilators and, in addition, mediates the action of various biologically active blood substances - histamine, serotonin, catecholamines, acetylcholine, etc. on the smooth muscles of the vascular wall, causing mainly their relaxation.
The most powerful vasodilator produced by the vascular endothelium is nitric oxide (NO). In addition to vasodilation, its main effects include inhibition of not only platelet adhesion and suppression of leukocyte emigration due to inhibition of the synthesis of endothelial adhesive molecules, but also the proliferation of vascular smooth muscle cells, as well as the prevention of oxidation, i.e., modification and, consequently, accumulation, of atherogenic lipoproteins in the subendothelium (antiatherogenic effect).
Nitric oxide in endothelial cells is formed from the amino acid L-arginine under the action of endothelial NO synthase. Various factors, such as acetylcholinesterase, bradykinin, thrombin, adenine nucleotides, thromboxane A2, histamine, endothelium, as well as an increase in the so-called. shear stresses as a result of, for example, intensification of blood flow, are able to induce NO synthesis by normal endothelium. NO produced by the endothelium diffuses through the internal elastic membrane to the smooth muscle cells and causes them to relax. The main mechanism of this action of NO is the activation of guanylate cyclase at the level of the cell membrane, which increases the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP), which determines the relaxation of smooth muscle cells. Then a number of mechanisms are activated to reduce cytosolic Ca++: 1) phosphorylation and activation of Ca++-ATPase; 2) phosphorylation of specific proteins leading to a decrease in Ca2+ in the sarcoplasmic reticulum; 3) cGMP-mediated inhibition of inositol triphosphate.
Other than NO, an important vasodilating factor produced by endothelial cells is prostacyclin (prostaglandin I2, PSH2). Along with its vasodilatory effect, PGI2 inhibits platelet adhesion, reduces the entry of cholesterol into macrophages and smooth muscle cells, and prevents the release of growth factors that cause thickening of the vascular wall. As is known, PGI2 is formed from arachidonic acid under the action of cyclooxygenase and PC12 synthase. PGI2 production is stimulated by various factors: thrombin, bradykinin, histamine, high-density lipoproteins (HDL), adenine nucleotides, leukotrienes, thromboxane A2, platelet-derived growth factor (PDGF), etc. PGI2 activates adenylate cyclase, which leads to an increase in intracellular cyclic adenosine monophosphate (cAMP).
In addition to vasodilators, coronary artery endothelial cells produce a number of vasoconstrictors. The most significant of these is endothelium I.
Endothelium I is one of the most potent vasoconstrictors capable of inducing prolonged smooth muscle contraction. Endothelial I is enzymatically produced in the endothelium from a prepropeptide. The stimulators of its release are thrombin, adrenaline and hypoxic factor, i.e. energy deficit. Endothelial I binds to a specific membrane receptor that activates phospholipase C and leads to the release of intracellular inositol phosphates and diacylglycerol.
Inositol triphosphate binds the receptor on the sarcoplasmic reticulum, which increases the release of Ca2+ into the cytoplasm. An increase in the level of cytosolic Ca2+ determines an increase in smooth muscle contraction.
In case of damage to the endothelium, the reaction of arteries to biologically active substances, vhch. acetylcholine, catecholamines, endothelium I, angiotensin II is perverted, for example, instead of dilatation of the artery, a vasoconstrictor effect develops under the action of acetylcholine.
The endothelium is a component of the hemostasis system. The intact endothelial layer has an antithrombotic/anticoagulant property. A negative (similar) charge on the surface of endotheliocytes and platelets causes their mutual repulsion, which counteracts platelet adhesion on the vascular wall. In addition, endothelial cells produce a variety of antithrombotic and anticoagulant factors PGI2, NO, heparin-like molecules, thrombomodulin (protein C activator), tissue plasminogen activator (t-PA), and urokinase.
However, with endothelial dysfunction developing under conditions of vascular damage, the endothelium realizes its prothrombotic/procoagulant potential. Pro-inflammatory cytokines and other inflammatory mediators can induce the production of substances in endotheliocytes that contribute to the development of thrombosis/hypercoagulability. When vessels are damaged, surface expression of tissue factor, plasminogen activator inhibitor, leukocyte adhesion molecules, and von WUlebrand(a) factor increases. PAI-1 (tissue plasminogen activator inhibitor) is one of the main components of the blood anticoagulation system, inhibits fibrinolysis, and is also a marker of endothelial dysfunction.
Endothelial dysfunction can be an independent cause of circulatory disorders in the organ, since it often provokes angiospasm or vascular thrombosis, which, in particular, is observed in some forms of coronary heart disease. In addition, regional circulation disorders (ischemia, severe arterial hyperemia) can also lead to endothelial dysfunction.
Intact endothelium constantly produces NO, prostacyclin, and other biologically active substances that can inhibit platelet adhesion and aggregation. In addition, it expresses the enzyme ADPase, which destroys ADP secreted by activated platelets, and thus, their involvement in the process of thrombosis is limited. The endothelium is capable of producing coagulants and anticoagulants, adsorbing numerous anticoagulants from blood plasma - heparin, proteins C and S.
When the endothelium is damaged, its surface changes from antithrombotic to prothrombotic. If the proadhesive surface of the subendothelial matrix is exposed, its components - adhesive proteins (von Willebrand factor, collagen, fibronectin, thrombospondin, fibrinogen, etc.) are immediately involved in the formation of a primary (vascular-platelet) thrombus, and then hemocoagulation.
Biologically active substances produced by endotheliocytes, primarily cytokines, can have a significant effect on metabolic processes by the endocrine type of action, in particular, change tissue tolerance to fatty acids and carbohydrates. In turn, violations of fat, carbohydrate and other types of metabolism inevitably lead to endothelial dysfunction with all its consequences.
In clinical practice, the doctor, figuratively speaking, "daily" has to deal with one or another manifestation of endothelial dysfunction, whether it be arterial hypertension, coronary heart disease, chronic heart failure, etc. It should be borne in mind that, on the one hand, endothelial dysfunction contributes to the formation and progression of a particular cardiovascular disease, and, on the other hand, this disease itself often exacerbates endothelial damage.
An example of such a vicious circle ("circulus vitiosus") can be a situation that is created in the conditions of the development of arterial hypertension. Prolonged exposure to increased blood pressure on the vascular wall can eventually lead to endothelial dysfunction, resulting in an increase in vascular smooth muscle tone and vascular remodeling processes (see below), one of the manifestations of which is the thickening of the media (the muscular layer of the vascular wall) and a corresponding reduction in vessel diameter. The active participation of endotheliocytes in vascular remodeling is due to their ability to synthesize a large number of different growth factors.
The narrowing of the lumen (the result of vascular remodeling) will be accompanied by a significant increase in peripheral resistance, which is one of the key factors in the formation and progression of coronary insufficiency. This means the formation (“closing”) of a vicious circle.
Endothelium and proliferative processes. Endothelial cells are able to produce both stimulants and inhibitors of the growth of smooth muscles of the vascular wall. With intact endothelium, the proliferative process in smooth muscles is relatively calm.
Experimental removal of the endothelial layer (deendothelialization) results in smooth muscle proliferation, which can be inhibited by repair of the endothelial lining. As mentioned earlier, the endothelium serves as an effective barrier to prevent smooth muscle cells from being exposed to various growth factors circulating in the blood. In addition, endothelial cells produce substances that have an inhibitory effect on proliferative processes in the vascular wall.
These include NO, various glycosaminoglycans, including heparin and heparin sulfate, as well as transforming growth factor (3 (TGF-(3). TGF-J3, being the strongest inducer of interstitial collagen gene expression, under certain conditions is able to inhibit vascular proliferation along feedback mechanism.
Endothelial cells also produce a number of growth factors that are able to stimulate the proliferation of vascular wall cells: Platelet Growth Factor (PDGF; Platelet Derived Growth Factor), so named because it was first isolated from platelets, is an extremely powerful mitogen that stimulates DNA synthesis and cell division; endothelial growth factor (EDGF; Endothelial-Cell-Derived Growth Factors), is able, in particular, to stimulate the proliferation of smooth muscle cells in atherosclerotic vascular lesions; fibroblast growth factor (FGF; Endothelial-Cell-Derived Growth Factors); endothelium; insulin-like growth factor (IGF; Insulin-Like Growth Factor); angiotensin II (in vitro experiments found that AT II activates the transcription factor of growth cytokines, thereby enhancing the proliferation and differentiation of smooth muscle cells and cardiomyocytes).
In addition to growth factors, molecular inducers of vascular wall hypertrophy include: mediator proteins or G-proteins that control the conjugation of cell surface receptors with effektor molecules of growth factors; receptor proteins that provide specificity of perception and influence the formation of second messengers cAMP and cGMP; proteins that regulate the transduction of genes that determine the hypertrophy of smooth muscle cells.
Endothelium and emigration of leukocytes. Endothelial cells produce a variety of factors that are important for the replenishment of leukocytes in areas of intravascular injury. Endothelial cells produce a chemotactic molecule, the monocyte chemotactic protein MCP-1, which attracts monocytes.
Endothelial cells also produce adhesion molecules that interact with receptors on the surface of leukocytes: 1 - intercellular adhesion molecules ICAM-1 and ICAM-2 (intercellular adhesion molecules), which bind to the receptor on B-lymphocytes, and 2 - vascular cell adhesion molecules -1 - VCAM-1 (vascular cellular adhesion molecule-1), interconnected with receptors on the surface of T-lymphocytes and monocytes.
Endothelium is a factor in lipid metabolism. Cholesterol and triglycerides are transported through the arterial system as part of lipoproteins, i.e. the endothelium is an integral part of lipid metabolism. Endotheliocytes can convert triglycerides into free fatty acids with the help of the enzyme lipoprotein lipase. The released fatty acids then enter the subendothelial space, providing an energy source for smooth muscle and other cells. Endothelial cells contain receptors for atherogenic low-density lipoproteins, which predetermines their participation in the development of atherosclerosis.
