Advertising on the portal

Endothelium histology. Basic Research

The human body is made up of many different cells. Some make up organs and tissues, and others make up bones. Endothelial cells play a huge role in the structure of the circulatory system of the human body.

What is endothelium?

The endothelium (or endothelial cells) is an active endocrine organ. Compared to the others, it is the largest in the human body and lines blood vessels throughout the body.

According to the classical terminology of histologists, endothelial cells are a layer that includes specialized cells that perform complex biochemical functions. They line the entire inside and their weight reaches 1.8 kg. The total number of these cells in the human body reaches one trillion.

Immediately after birth, the density of endothelial cells reaches 3500-4000 cells/mm2. In adults, this figure is almost two times lower.

Previously, endothelial cells were considered only a passive barrier between tissues and blood.

Existing forms of endothelium

Specialized forms of endothelial cells have certain structural features. Depending on this they distinguish:

  • somatic (closed) endothelial cells;
  • fenestrated (perforated, porous, visceral) endothelium;
  • sinusoidal (large porous, large window, hepatic) type of endothelium;
  • ethmoidal (intercellular slit, sinus) type of endothelial cells;
  • high endothelium in postcapillary venules (reticular, stellate type);
  • endothelium of the lymphatic bed.

The structure of specialized forms of endothelium

Endotheliocytes of the somatic or closed type are characterized by tight gap junctions and, less commonly, by desmosomes. In the peripheral areas of such endothelium, the thickness of the cells is 0.1-0.8 microns. In their composition, one can notice numerous micropinocytotic vesicles (organelles that store useful substances) of a continuous basement membrane (cells separating connective tissues from the endothelium). This type of endothelial cells is localized in the exocrine glands, central nervous system, heart, spleen, lungs, and large vessels.

Fenestrated endothelium is characterized by thin endotheliocytes, which contain through diaphragmatic pores. The density in micropinocytotic vesicles is very low. A continuous basement membrane is also present. These endothelial cells are most often found in capillaries. Cells of such endothelium line capillary beds in the kidneys, endocrine glands, mucous membranes of the digestive tract, and choroid plexuses of the brain.

The main difference between the sinusoidal type of vascular endothelial cells and the rest is that their intercellular and transcellular channels are very large (up to 3 µm). The basement membrane is characterized by discontinuity or its complete absence. Such cells are present in the vessels of the brain (they are involved in the transport of blood cells), the adrenal cortex and the liver.

Cribriform endothelial cells are rod-shaped (or spindle-shaped) cells that are surrounded by a basement membrane. They also take an active part in the migration of blood cells throughout the body. Their location is the venous sinuses in the spleen.

The reticular type of endothelium includes stellate cells, which are intertwined with basolateral processes of a cylindrical shape. The cells of this endothelium provide transport of lymphocytes. They are part of the vessels passing through the organs of the immune system.

Endothelial cells, which are found in the lymphatic bed, are the thinnest of all types of endothelium. They contain increased levels of lysosomes and contain larger vesicles. There is no basement membrane at all, or it is discontinuous.

There is also a special endothelium that lines the back surface of the cornea of ​​the human eye. The endothelial cells of the cornea transport fluid and solutes into the cornea and also maintain its dehydrated state.

The role of the endothelium in the human body

Endothelial cells, which line the inside of the walls of blood vessels, have an amazing ability: they increase or decrease their number, as well as their location, in accordance with the requirements of the body. Almost all tissues require blood supply, which in turn depends on endothelial cells. They are responsible for creating a highly adaptable life support system that branches into all areas of the human body. It is thanks to this ability of the endothelium to expand and restore the network of blood vessels that the healing process and tissue growth occur. Without this, wound healing would not occur.

Thus, endothelial cells lining all vessels (from the heart to the smallest capillaries) ensure the passage of substances (including leukocytes) through tissues into the blood, and also back.

In addition, laboratory studies of embryos have shown that all large blood vessels and veins are formed from small vessels that are built exclusively from endothelial cells and basement membranes.

Endothelial functions

First of all, endothelial cells maintain homeostasis in the blood vessels of the human body. The vital functions of endothelial cells include:

  • They act as a barrier between blood vessels and blood, essentially serving as a reservoir for the latter.
  • Such a barrier has what protects the blood from harmful substances;
  • The endothelium senses and transmits signals carried by the blood.
  • It integrates, if necessary, the pathophysiological environment in the vessels.
  • Performs the function of a dynamic regulator.
  • Controls homeostasis and restores damaged blood vessels.
  • Maintains the tone of blood vessels.
  • Responsible for the growth and remodeling of blood vessels.
  • Detects biochemical changes in the blood.
  • Recognizes changes in carbon dioxide and oxygen levels in the blood.
  • Ensures blood fluidity by regulating its coagulation components.
  • Control blood pressure.
  • Forms new blood vessels.

Endothelial dysfunction

As a result of endothelial dysfunction, the following may develop:

  • atherosclerosis;
  • hypertension;
  • coronary insufficiency;
  • diabetes and insulin resistance;
  • renal failure;
  • asthma;
  • adhesive disease of the abdominal cavity.

All these diseases can only be diagnosed by a specialist, so after 40 years you should regularly undergo a full examination of the body.


Owners of patent RU 2309668:

The 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 and 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, and an occlusion test is performed, during which a cuff is applied proximally to the location 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 two-channel sensor unit that is capable of recording pulse curves from peripheral arteries. A pressure creation unit configured to create increasing stepwise pressure in the cuff. An electronic unit configured to determine the pressure in the cuff corresponding to the maximum amplitude of the plethysmographic signal, and control the pressure generating unit to establish a pressure in the cuff corresponding to the amplitude of the plethysmographic signal that is a predetermined percentage of the maximum amplitude, wherein the sensor unit is connected to the electronic unit, to the output of which is connected to a pressure generating unit. The claimed invention makes it possible to increase the reliability of the assessment of endothelial function, regardless of the patient’s blood pressure. 2 n. and 15 salary f-ly, 6 ill.

The invention relates to medicine, namely to functional diagnostics, and allows early detection of the presence of cardiovascular diseases and monitoring the effectiveness of therapy. The invention will allow assessing the state of the endothelium and, based on this assessment, solving the issue of early diagnosis of cardiovascular diseases. The invention can be used when conducting large-scale clinical examination of the population.

Recently, the task of early detection of cardiovascular diseases has become increasingly important. For this purpose, a wide range of diagnostic tools and methods described in patent and scientific literature are used. Thus, US patent No. 5,343,867 discloses a method and device for the early diagnosis of atherosclerosis using impedance plethysmography to identify the characteristics of the pulse wave in the vessels of the lower extremities. It has been shown that blood flow parameters depend on external pressure applied to the artery under study. The maximum amplitude of the plethysmogram is largely determined by the value of transmural pressure, which is the difference between the blood pressure inside the vessel and the pressure applied externally using 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: pressure from the cuff is transmitted to the outer wall of the artery and balances the intra-arterial pressure from the inner wall of the artery. In this case, 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 arterial diameter at the same pulse pressure becomes large. This phenomenon can be easily seen on the oscillometric curve taken when recording blood pressure. In this curve, maximum oscillation occurs when the cuff pressure is equal to the mean arterial pressure.

US patent No. 6322515 discloses a method and device for determining a number of parameters of the cardiovascular system, including those used to assess the condition of the endothelium. Photodiodes and photodetectors were used here as a sensor to determine the pulse wave, and an analysis of photoplethysmographic (PPG) curves recorded on the digital artery before and after the test with reactive hyperemia was carried out. When recording these curves, a cuff was placed on the finger over the optical sensor, in which a pressure of 70 mm Hg was created.

US Patent No. 6,939,304 discloses a method and device for non-invasive assessment of endothelial function using a PPG sensor.

US Pat. No. 6,908,436 discloses a method for assessing the condition of the endothelium by measuring the velocity of pulse wave propagation. For this, a two-channel plethysmograph is used, sensors are installed on the phalanx of the finger, and occlusion is created using a cuff placed on the shoulder. Changes in the state of the arterial wall are assessed by the delay in propagation of the pulse wave. A delay of 20 ms or more is considered a test confirming normal endothelial function. The delay is determined by comparison with the PPG curve recorded on the hand on which the occlusion test was not performed. However, the disadvantages of the known method are the determination of the delay by measuring the displacement in the minimum region immediately before the systolic rise, i.e. in an area that is highly variable.

The closest analogue to the claimed method and device is the method and device for non-invasive determination of changes in the physiological state of the patient, described in RF patent No. 2220653. The known method consists of 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, then recording the pulse wave using the PPG method. on both hands, after which an amplitude analysis of the PPG curve is carried out in relation to the obtained measurements before and after clamping, and 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 allow for high reliability of the studies performed 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. Assessment of the state of the endothelium is a “barometer”, a glance at which allows for early diagnosis of CVD. Such diagnostics will allow us to move away from the approach where it is necessary to carry out a series of biochemical tests (determining the level of cholesterol, low and high density lipoproteins, homocysteine, etc.) to identify the presence of a risk factor. It is more economically feasible to screen the population at the first stage to use an integral indicator of the risk of developing the disease, which is an assessment of the condition of the endothelium. Assessing the state of the endothelium is also extremely important for objectifying the therapy being carried out.

The problem to which the claimed inventions are aimed is to create a physiologically based, non-invasive method and device for reliably determining the state of the endothelial function of the patient being examined, providing a differentiated approach depending on the patient’s condition and based on a system for converting, amplifying and recording the PPG signal under the action of the optimal the value of a given pressure or force locally applied to the located artery before and after the occlusion test.

The technical result that is achieved when using the claimed device and method is to increase the reliability of the assessment of endothelial function, regardless of the patient’s blood pressure.

The technical result in terms of the method is achieved by reducing the transmural pressure in the limb, recording the amplitude of plethysmographic signals at various pressures, determining the pressure at which the amplitude of the PG signal is maximum, reducing the pressure to a value corresponding to a given % of the maximum amplitude, carrying out occlusion test, during which a pressure is created in a cuff placed proximally from the location of the limb that exceeds the systolic pressure of the subject by at least 50 mm Hg, and occlusion is carried out for at least 5 minutes.

The technical result is enhanced by the fact that transmural pressure is reduced by applying a cuff in which pressure is created to the area of ​​the limb.

The pressure on the limb tissue is increased discretely in increments of 5 mmHg. and a step duration of 5-10 seconds, the amplitude of the PG signal is recorded.

To reduce transmural pressure in the located artery, mechanical force is used, locally applied to the tissues of the limb.

To reduce transmural pressure in the located artery, hydrostatic pressure is reduced by raising the limb to a given height relative to the level of the heart.

After selecting the transmural pressure value at which the amplitude of the PG signal is 50% of the maximum increase in the PG signal, suprasystolic pressure is created in the occlusion cuff installed proximally from the located artery, and the plethysmographic signal is recorded.

After at least 5 minutes of exposure to the occlusion cuff installed proximally from the artery being located, the pressure in it is reduced to zero, and changes in the PG signal are recorded simultaneously through two reference and test channels for at least 3 minutes.

The recorded plethysmographic signal after the occlusion test is analyzed using simultaneous amplitude and time analysis based on data obtained from two reference and test channels.

When carrying out amplitude analysis, 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 resulting maximum at various values ​​of transmural pressure are compared with the maximum signal value obtained after the occlusion test.

When conducting a time analysis, plethysmographic curves obtained from the reference and test channels are compared, a signal normalization procedure is carried out, 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 capable of recording pulse curves from peripheral arteries, a pressure creation unit, made with the ability to create increasing stepwise pressure in the cuff, and an electronic unit, made with the ability to determine pressure in the cuff corresponding to the maximum amplitude of the PG signal and control of the pressure creation unit to establish pressure in the cuff corresponding to the amplitude of the PG signal, which is a given 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 creation unit is connected.

The technical result is enhanced by the fact that the pressure creation unit is designed to create stepwise increasing pressure in the cuff in increments of 5 mm Hg. Art. and a step duration of 5-10 seconds.

The sensor unit in each channel includes an infrared diode and a photodetector, located with the ability to register a light signal passing through the location area.

The sensor unit in each channel includes an infrared diode and a photodetector located with the ability to register the scattered light signal reflected from the location area.

The sensor unit includes impedance electrodes, or Hall sensors, or an elastic tube filled with electrically conductive material.

The photodetector is connected to a filter that has the ability to isolate the pulse component from the general signal.

The sensor unit includes a means for maintaining a given temperature of the location of the body area.

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 invention and the possibility of achieving a technical result achieved as a result of their use will be more clear when describing an example implementation with reference to the positions of the drawings, where figure 1 illustrates the dynamics of indicators of volumetric blood flow and the diameter of the brachial artery during an occlusion test, on Fig.2 shows a diagram of the formation of a PPG signal, Fig.3 shows a PPG curve, Fig.4 shows a family of PPG curves obtained at different values ​​of transmural pressure in patients in the control group, Fig.5 shows the effect of changes in hydrostatic pressure on the amplitude of the PPG signal, and Fig. 6 shows 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 establish the pressure in the cuff 1, corresponding to the amplitude of the PG signal, which is a specified percentage (50%) of the maximum increase in amplitude. It is possible to implement the sensor unit in several variants: in the first variant, the infrared LED 2 and the photodetector 3 are located with the ability to register 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 ability to register 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 electrically conductive material.

Assessment of endothelial function is carried out on the basis of registration of the PG signal obtained using a sensor unit installed on the upper limbs of the patient being examined, followed by electrical conversion of the received signal during a linear increase in pressure in cuff 1 (or the magnitude of the force locally applied 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 carried out at a fixed value of pressure or force. In this case, the sensor block is installed on the inside of the cuff 1 or located at the end of the device that creates a force in the area of ​​​​the projection of the artery onto the surface of the skin. To automatically set this pressure, feedback is used on the amplitude of the PG signal coming from the digital-to-analog converter 8 through the controller 9 to the compressor 11 of the pressure generation unit.

An occlusion test is carried out using a cuff installed proximally (upper arm, forearm, wrist) relative to the artery being located (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 one.

The claimed method for determining the state of the endothelial function of the patient being examined includes two main stages: the first allows one to obtain a series of plethysmographic curves recorded at different pressures in cuff 1 (or 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 conducting an 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 blood 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; accordingly, with an increase in transmural pressure, a 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 virtually unchanged.

A change in smooth muscle tone is realized not only in the form of narrowing or dilatation of the artery, but also leads, accordingly, to an increase in the rigidity 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 is manifested in the PPG as an increase in the signal amplitude. The maximum amplitude occurs when the transmural pressure is zero. This is shown schematically in Figure 4, where the S-shaped deformation curve shows that the maximum volume increase is determined at a transmural pressure close to zero. With equal waves of pulse pressure applied to different sections of the deformation curve, the maximum plethysmographic signal is observed in the region close to the zero value of transmural pressure. In patients in the control group, comparable in age and diastolic pressure to the group of people with clinical manifestations of ischemic disease, the increase in signal amplitude with changes in transmural pressure can be more than 100% (Fig. 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. The smooth muscle tone of the arteries can be considered primarily as a viscous component, while elastin and collagen fibers represent a purely elastic component of the structure of the vascular wall. By reducing smooth muscle tone as we approach zero values ​​of transmural pressure, we seem to reduce the contribution of the viscous component of smooth muscles to the deformation curve. This technique allows not only to conduct a more detailed analysis of the deformation curve of the elastic components of the arterial vascular wall, but also to register the phenomenon of reactive hyperemia under more favorable conditions after an occlusion test.

The magnitude of the increase in the diameter of the afferent artery is associated with the functioning of endothelial cells. An increase in shear stress after an occlusion test leads to an increase in the synthesis of nitric oxide (NO). A so-called “flow-induced dilatation” 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 vessel dilatation is determined by the following sequence of events: occlusion, increased blood flow, the effect of shear stress on endothelial cells, nitric oxide synthesis (as an adaptation to increased blood flow), and the effect of NO on smooth muscle.

The maximum blood flow is achieved 1-2 seconds after the occlusion is removed. It should be noted that with simultaneous monitoring of the amount of blood flow and the diameter of the artery, the amount of blood flow initially increases, and only after that the diameter of the vessel changes (Fig. 1). After quickly (several seconds) reaching the maximum blood flow velocity, the diameter of the artery increases, reaching a maximum after 1 minute. After which it returns to its original value within 2-3 minutes. Using the example of the characteristics of the state of the elastic module of the arterial wall in patients with arterial hypertension, we can make an assumption about the possible participation of the initial stiffness of the artery in the manifestation of the response of endothelial cells to the occlusion test. It cannot be excluded that, with the same production of nitric oxide by endothelial cells, the manifestation of the response by smooth muscle cells of the artery will be determined by the initial state of the elasticity modulus of the arterial wall. To normalize 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 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 the occlusion 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 flow-dependent dilatation. The method is based on an increase in optical density associated with a pulse 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 with PPG the optical sensor does not record 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 a PPG signal. The photodiode registers the light flux passing through the located area of ​​the finger tissue. With each pulse wave, the finger artery expands, increasing blood volume. Blood hemoglobin absorbs IR radiation to a large extent, 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. You can see two peaks 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, compressor 11, based on a signal from controller 9, creates pressure in cuff 1. The pressure increases in steps of 5 mm Hg, the duration of each step is 5-10 seconds. With increasing pressure, 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 of the signal coming from the photodetector 3 is recorded. The signal from the output of the converter 4 is amplified in the amplifier 5 and filtered in the filter 6 to cut out interference with an industrial frequency of 50 Hz and its harmonics. The main signal amplification 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. 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) reducing transmural pressure by applying pressure to part of the finger (air cuff, 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 external force on the vessel wall. In a simplified version of assessing the state of the endothelium, it is possible to eliminate the complex automation scheme, and only by raising and lowering the hand, determine the average pressure based on the maximum amplitude of the plethysmographic signal, reach the linear section of the compliance curve (50% of the maximum increase) and then conduct an occlusion test. The only disadvantage of this approach is the need to position the hand and perform occlusion with the hand elevated.

With a decrease in transmural pressure, the pulse component of the PPG increases, which corresponds to an increase in the compliance of the artery under study. When exposed to a sequence of increasing pressures applied to the finger, it is possible, on the one hand, to see the severity of the autoregulatory reaction, and on the other hand, to select optimal conditions (based on the value of transmural pressure) for collecting information when conducting an occlusion test (selecting the steepest section on the arterial compliance curve );

2) creating occlusion of the artery by applying suprasystolic pressure (at 30 mmHg) 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 through two reference and test channels for at least 3 minutes. When carrying out amplitude analysis, the signal amplitudes in the reference and test channels are compared, the rate of increase in the signal amplitude in the test channel, the ratio of signal amplitudes, the maximum obtained at various values ​​of transmural pressure, with the maximum signal value obtained after an occlusion test. When conducting a time analysis, the plethysmographic curves obtained from the reference and test channels are compared, a 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 (pressure applied to the vessel from the outside is equal to mean arterial pressure). The calculation was carried out as follows - diastolic pressure plus 1/3 of pulse pressure. This response of the artery to external pressure is not endothelium dependent. The method of selecting pressure applied externally to the artery not only makes it possible to carry out a test with reactive hyperemia based on the dynamics of the PPG signal in the most optimal area of ​​arterial compliance, but also has its own diagnostic value. Recording a family of PPG curves at different values ​​of transmural pressure allows one to obtain information about the rheological characteristics of the artery. This information makes it possible to distinguish changes associated with the autoregulatory effect of the smooth muscle apparatus of the arterial 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 the larger volume of blood located in the localized area. The pulse component of the signal reflects the increase in blood volume during systole. The amplitude of the PPG 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. Complete parallelism between the increase in vessel diameter and wall compliance with changes in transmural pressure is not observed.

At low transmural pressure, the arterial wall becomes less rigid compared to its mechanical properties determined at physiological blood pressure values.

Optimizing the test based on 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 pharmacological therapy aimed at correcting endothelial function disorders.

When the pressure in the cuff increases to 100 mm Hg. There was a constant increase in the signal, the maximum signal amplitude was determined at 100 mmHg. A further increase in pressure in the cuff led to a decrease in the amplitude of the PPG signal. Reduced pressure to 75 mm Hg. was accompanied by a decrease in the amplitude of the PPG signal by 50%. The pressure in the cuff also changed the shape of the PPG signal (see Fig. 3).

The change in the shape of the PPG signal consisted of a sharp increase in the rate of increase of the systolic rise with a simultaneous delay in the start of the rise. These shape changes reflect the influence of the cuff on the passage of the pulse pressure wave. This phenomenon occurs due to the subtraction of the pressure value of the cuff from the pulse wave.

Raising the arm relative to the “point of equal pressure” (heart level) allows you to avoid using externally applied pressure (tension) using a cuff. Raising the hand from the “point of equal pressure” to a position extended upward increases the amplitude of the PPG. Subsequent lowering of the hand to the initial level reduces the amplitude to the initial level.

An important factor influencing the magnitude of transmural pressure is gravity. Transmural pressure in the digital artery of a raised hand is less than the pressure in the same artery located at the level of the heart by the product of blood density, gravity acceleration and distance from the “pressure equality point”:

where Ptrh is the transmural pressure in the digital artery of the raised hand,

Ptrho - transmural pressure in the digital artery located at the level of the heart, p - blood density (1.03 g/cm), g - gravity acceleration (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 pressure equality,” the pressure of a standing person with his arm raised is 66 mm Hg. below the average digital artery pressure measured at the level of the heart.

Thus, transmural pressure can be reduced by increasing the externally applied pressure or decreasing the pressure in the vessel. Reducing pressure in the digital artery is quite easy. To do this, you need to raise your hand above the level of your heart. By 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 decrease to 30 mm Hg, whereas when the hand is at the level of the heart it is 90 mm Hg. Transmural pressure in the arteries of the leg can be four times greater than in the arteries of the raised arm. The influence 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 performing an occlusion test is selected individually for each patient,

2) information is provided on the viscoelastic properties of the arterial bed (based on the dependence of the amplitude of the PG signal on pressure (force)),

3) the signal-to-noise ratio is improved,

4) the occlusion test is carried out 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 recording a family of PPG curves at different values ​​of transmural pressure,

6) inventions increase the sensitivity of the test, and therefore the reliability of the assessment of endothelial function,

7) make it possible to identify pathology at the earliest stages of endothelial dysfunction,

8) allow you to reliably assess the effectiveness of pharmacotherapy.

1. A method for non-invasive determination of endothelial function, including performing an occlusion test, during which a pressure exceeding the systolic pressure of the subject is created in a cuff placed proximally from the location of the limb, and occlusion is carried out for 5 minutes, characterized in that at the first stage decrease in transmural pressure in the limb, record the amplitudes of plethysmographic signals at various pressures, determine the pressure at which the amplitude of the plethysmographic signal is maximum, then reduce the pressure to a value corresponding to a given percentage of the maximum amplitude, at the second stage an occlusion test is carried out, and a pressure exceeding systolic is created the test subject's pressure by at least 50 mm Hg, then after the occlusion test, the recorded plethysmographic signal is analyzed using simultaneous amplitude and time analysis using 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 transmural pressure in the located artery, hydrostatic pressure is reduced by raising the limb to a given height relative to the level of the heart.

5. The method according to claim 1, characterized in that after selecting the transmural pressure value, at which the amplitude of the plethysmographic signal is 50% of the maximum possible value, suprasystolic pressure is created in the occlusion cuff installed proximally from the located artery, and the plethysmographic signal is recorded.

6. The method according to claim 5, characterized in that after at least 5 minutes of exposure of the occlusion cuff installed proximally from the located artery, the pressure in it is reduced to zero, and the registration of changes in the plethysmographic signal is carried out simultaneously in 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 amplitude values ​​in the reference and test channels are compared, the rate of increase of the signal amplitude in the test channel, the ratio of signal amplitudes, the maximum obtained at various values ​​of transmural pressure with the maximum signal value, obtained after performing an occlusion test.

8. The method according to claim 1, characterized in that when conducting 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.

9. A device for non-invasive determination of endothelial function, including a two-channel sensor unit capable of recording pulse curves from peripheral arteries, a pressure creation unit capable of creating stepwise pressure in the cuff, and an electronic unit capable of determining the pressure in the cuff , corresponding to the maximum amplitude of the plethysmographic signal, and controlling the pressure generation unit to establish a pressure in the cuff corresponding to the amplitude of the plethysmographic signal, constituting a predetermined percentage of the maximum amplitude, wherein 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 creation unit is configured to create stepwise increasing pressure in the cuff with a step of 5 mmHg and a step duration of 5-10 s.

11. The device according to claim 9, characterized in that each channel of the sensor unit includes an infrared diode and a photodetector located with the ability to register a light signal passing through the located area.

12. The device according to claim 9, characterized in that each channel of the sensor unit includes an infrared diode and a photodetector located with the ability to register the scattered light signal reflected from the location 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 electrically conductive material.

14. The device according to claim 11, characterized in that the photodetector is connected by a filter capable of isolating the pulse component from the general 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 individuals over 6 years of age of different fitness levels 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

Details

Endothelium is the intima of blood vessels. It performs a number of important functions, including: regulates the tone of blood vessels, promotes changes in their diameter, is a sensor of damage to the vascular wall and can trigger the blood clotting mechanism.

1. General plan of the structure of the vascular wall.

2. The main functions of the vascular endothelium.

  • Regulation of vascular tone and vascular resistance
  • Regulation of blood flow
  • Regulation of angiogenesis
  • Implementation of the inflammation process

3. The main functions of the endothelium are realized:

1) A shift in the secretory function of the endothelium towards vasodilatory factors (90% accounted for nitric oxide).

2) Inhibition:

  • Platelet aggregations
  • White blood cell adhesion
  • Smooth muscle proliferation

The main functions of the endothelial layer of a vascular cell are determined by its synthetic phenotype - a set of vasoactive factors synthesized by the endothelium.

4. With endothelial dysfunction, the following is observed:

1) Shift in the secretory function of the endothelium towards vasoconstrictor factors

2) Gain:

  • platelet aggregation
  • white blood cell adhesion
  • smooth muscle cell proliferation

Which leads to a decrease in the vascular lumen, thrombus formation, the appearance of a focus of inflammation and hypertrophy of the vascular wall.

5. Regulation of blood fluidity with the participation of the endothelium is normal.

6. A shift in the synthetic activity of the endothelial cell towards a procoagulant phenotype when the integrity of the endothelium is disrupted or an inflammatory process occurs.

7. VASCULAR ENDOTHELIUM SYNTHESIS AND RELEASES CONTRACTOR AND DILIATOR VASOACTIVE FACTORS:

8. Types of action of vasoactive factors synthesized by the endothelium of the vascular wall.

9. The main pathways of arachidonic acid metabolism.

Cyclooxygenase pathway
Lipoxygenase pathway
Epoxygenase pathway
Transacylase (membrane) pathway

Activation of phospholipase A2 (bradykinin) stimulates the release of arachidonic acid into the soluble part of the cell and its metabolism

10. Cooperative method of activation of arachidonic acid.

11. Metabolism of arachidonic acid (AA) with the participation of phospholipase A2 (PLA2).

==>>Inflammation.

12. Metabolites of arachidonic acid via the cyclooxygenase pathway.

13. The mechanism of action of non-steroidal anti-inflammatory drugs with analgesic effect.

14. Types of cyclooxygenases. Their stimulation and inhibition.

Cyclooxygenase type I (inhibited by paracetamol) and type II (inhibited by diclofenac)

15. The mechanism of action of prostacyclin (PG2) on vascular smooth muscle.

16. Scheme of synthesis of endogenous cannabinoids.

Endogenous cannabinoids (NAEs) - (anandamide) are metabolized to form arachidonic acid and its subsequent degradation.

The mechanism of action of the endogenous cannabinoid – anandamide on the vascular wall:

Rapid degradation in the endothelium reduces the expansion potential of endocannabinoids.

The effect of anandamide on the resistance of the perfused intestinal vascular bed (A) and the isolated resistive mesenteric vessel (B).

Scheme of a possible metabolic pathway for anandamide, inhibiting its direct vasodilatory effect on vascular smooth muscle.

17. Endothelium-dependent vasodilation.

Nitric oxide synthesis: the key element is NO synthase (constitutive - always works and inducible - activated under the influence of certain factors)

18. Isoforms of NO synthases: neuronal, inducible, endothelial and mitochondrial.

Structure of nitric oxide synthase isoforms:

mtNOS is the alpha form of nNOS, characterized by a phosphorylated C-terminus and two altered amino acid residues.

19. The role of NO synthases in the regulation of various body functions.

20. Scheme of activation of NO and cGMP synthesis in an endothelial cell.

21. Physiological and humoral factors that activate the endothelial form of NO synthase.

Factors determining the bioavailability of nitric oxide.

Participation of nitric oxide in the oxidative stress response.

The effect of pyroxynitrite on cell proteins and enzymes.

22. Nitric oxide synthesis by endothelial cells and the mechanism of vascular smooth muscle dilatation.

23. Guanylate cyclase is an enzyme that catalyzes the formation of cGMP from GTP, structure and regulation. The mechanism of vessel dilation with the participation of cGMP.

24. Inhibition of cGMP Rho-kinase pathway of vascular smooth muscle contraction.

25. Vasoactive factors synthesized by the endothelium and ways of realizing their effect on vascular smooth muscle.

26. Discovery of endothelin, an endogenous peptide with vasoactive properties.

Endothelin is an endogenous peptide synthesized by endothelial cells of the vascular system.

Endothelin is a 21-membered peptide with vasoconstrictor properties.

Structure of endothelin-1, Endothelin family: ET-1, ET-2, ET-3.

Endothelin:

Expression of different forms of the peptide in tissues:

  • Endothelin-1 (endothelium and vascular smooth muscle, cardiac myocytes, kidney, etc.)
  • Endothelin-2 (kidney, brain, gastrointestinal tract, etc.)
  • Endothelin-3 (intestine, adrenal glands)

Mechanism of synthesis in tissues: three different genes -
Preproendothelin-->big endothelin-->endothelins
*furin-like endopept. endothelinprev. farms
(cell surface, intracellular visicles)
Types of receptors and effects:
Eta (smooth muscle - contraction)
ETB (endothelium-secretion endothelium-factory expansion factor smooth muscle-contraction)
Content in tissues and blood: fm/ml
an increase of 2-10 times in heart failure, pulmonary hypertension, renal failure, subarachnoid hemorrhage, etc.

27. Endothelin synthesis by endothelial cells and the mechanism of vascular smooth muscle contraction.

28. The mechanism of implementation of the action of endothelin on vascular smooth muscle in normal and pathological conditions.

29. Pathological role of endothelin.

  • vasoconstriction
  • hypertrophy
  • fibrosis
  • inflammation

30. The main factors of humoral regulation of vascular tone, mediating their effect through changes in the secretory function of the endothelium.

  • Catecholamines (adrenaline and norepinephrine)
  • Angiothesin-renin system
  • Endothelin family
  • ATP, ADP
  • Histamine
  • Bradykinin
  • Thrombin
  • Vasopressin
  • Vasoactive intensinal peptide
  • Colcitonin gene binding peptide
  • Natriuretic peptide
  • Nitric oxide

What is endothelium?
Endothelium - these are special cells lining the inner
the surface of blood, lymphatic vessels and cardiac cavities. It separates the blood flow from the deeper layers of the vascular wall and serves as a boundary between them.

Of great importance for the normal functioning of various systems of the body, including the nervous system, is the adequate receipt of “nutrients” by all its cells and neurons through the bloodstream.
For what, the condition of large, small and tiny vessels, and especially their inner wall - the endothelium, is paramount.

The endothelium is an active organ. It continuously produces a large amount of biologically active substances (BAS). They are important for the process of blood clotting, regulation of vascular tone, and stabilization of blood pressure. "Endothelial" biologically active substances are involved in the process of brain metabolism and are important for the filtration function of the kidneys and myocardial contractility.

A special role belongs to the state of endothelial integrity. While it is not damaged, it actively synthesizes various BAS factors.
Anti-clotting, at the same time dilate blood vessels, and prevent the growth of smooth muscles, which can narrow this lumen.
Healthy endothelium synthesizes the optimal amount of nitric oxide (NO), which maintains blood vessels in a state of dilation and ensures adequate blood flow, especially to the brain.

NO is an active angioprotector, helps prevent pathological restructuring of the vascular wall, progression of atherosclerosis and arterial hypertension, antioxidant, inhibitor of platelet aggregation and adhesion.

Angiotensin converting enzyme (ACE) is also formed when the endothelium is damaged. It converts the inactive substance angiotensin I into the active substance angiotensin II.
Angiotensin II affects the increase in vascular tone, promotes the development of arterial hypertension, the conversion of useful NO intoactive oxidative radical with a damaging effect.

The endothelium synthesizes factors involved in blood clotting (thrombomodulin, von Willebrand factor, thrombospondin).
Thus, biologically active substances constantly produced by the endothelium are the basis for adequate blood flow. They affect the state of the vascular wall (spasm or relaxation) and the activity of coagulation factors.

A normally functioning endothelium prevents platelet adhesion (their gluing to the vessel wall), platelet aggregation (their gluing together), reduces blood coagulation and spasm of blood vessels.

But when its structure changes, functional disorders also occur. The endothelium “produces” harmful active substances - aggregates, coagulants, vasoconstrictors - more than necessary. They have an adverse effect on the functioning of the entire circulatory system and lead to diseases, including ischemic heart disease, atherosclerosis, arterial hypertension and others.
An imbalance in the production of active substances is called endothelial dysfunction (ED).
DE leads to micro- and macro-angiopathy. In diabetes mellitus, microangiopathy leads to the development of retino- and nephropathy, macroangiopathy leads to the development of atherosclerosis with damage to the vessels of the heart, brain, peripheral arteries of the extremities, most often the lower ones. Any angiopathy is characterized by Virchow's triad - changes in the endothelium, disorders of the blood coagulation and anticoagulation system, and slowing of blood flow.
DE is an imbalance between the production of vasodilating (vasodilator), antithrombotic, angioprotective factors on the one hand and vasoconstrictor (vasoconstrictor), prothrombic, proliferative factors on the other.

DE is, on the one hand, one of the important pathogenetic mechanisms

the development of vascular diseases of the brain, heart and other organs (for example, ischemic heart disease,), on the other hand, is an independent risk factor for these problems.

The more pronounced it is, the more the brain (and all other organs and tissues) vessels, especially small and minute ones, suffer. Microcirculation and the cells receiving the necessary nutrition are disrupted.

Indirectly, the severity of DE can be determined by certain biochemical blood parameters - the level of factors that damage the endothelium. They are called mediators of endothelial damage.


These include hyperglycemia, hyperhomocysteinemia, increased serum triglycerides, microalbuminuria, altered blood cytokine levels, and decreased blood NO concentrations.
The degree of change in these indicators correlates with the degree of endothelial dysfunction, and, consequently, with the severity of vascular disorders and the degree of risk of various complications (heart attacks, , IHD, etc.).

Timely identification of indicators of endothelial damage will allow timely measures to be taken to reduce them and more effectively carry out primary and secondary prevention of various diseases of the circulatory system and vascular diseases of the brain.

Verification: 4b3029e9e97268e2

October 31, 2017 No comments

The endothelium and its basement membrane act as a histohematic barrier, separating blood from the intercellular environment of surrounding tissues. In this case, endothelial cells are connected to each other by dense and slit-like junctional complexes. Along with the barrier function, the endothelium ensures the exchange of various substances between the blood and surrounding tissues. The metabolic process at the capillary level is carried out using pinocytosis, as well as the diffusion of substances through the fines and pores. Endotheliocytes 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 diffusion 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 layer of smooth muscle.

Thus, the endothelial lining can be traversed by three tightly regulated pathways. First, some molecules can reach smooth muscle cells by penetrating through the junctions between endothelial cells. Secondly, molecules can be transported across endothelial cells using 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), the adhesive properties of the inner surface of the vessels, as well as metabolic processes in the myocardium. These and other functional capabilities of endothelial cells are determined by their fairly high ability to produce various biologically active molecules, including cytokines, anti- and procoagulants, antimitogens, etc., from the lumen of the vessel to the subintimal layers of its wall -

The endothelium is capable of producing and secreting a number of substances that have both vasoconstrictor and vasodilator effects. With the participation of these substances, self-regulation of vascular tone occurs, which significantly complements the function of vascular neuroregulation.

The intact vascular endothelium synthesizes vasodilators and, in addition, mediates the effect of various biologically active substances in the blood - 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 adhesion molecules, but also the proliferation of vascular smooth muscle cells, as well as the prevention of oxidation, i.e. modification and, therefore, 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 stress as a result, for example, of increased blood flow, can 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 aimed at reducing 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 suppression of inositol triphosphate.

Another important vasodilator factor, besides NO, produced by endothelial cells is prostacyclin (prostaglandin I2, РШ2). Along with its vasodilating effect, PGI2 inhibits platelet adhesion, reduces the entry of cholesterol into macrophages and smooth muscle cells, and also 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 lipoprotein (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, endothelial cells of the coronary arteries produce a number of vasoconstrictors. The most significant of them is endothelium I.

Endothelium I is one of the most powerful vasoconstrictors, capable of causing prolonged contraction of smooth muscle. Endothelial I is enzymatically produced in the endothelium from prepropeptide. The stimulators of its release are thrombin, adrenaline and hypoxic factor, i.e. energy deficiency. Endothelial I binds to a specific membrane receptor, which activates phospholipase C and leads to the release of intracellular inositol phosphates and diacylglycerol.

Inositol triphosphate binds to a receptor on the sarcoplasmic reticulum, which increases the release of Ca2+ into the cytoplasm. An increase in the level of cytosolic Ca2+ determines increased contraction of smooth muscle.

When the endothelium is damaged, the reaction of the arteries to biologically active substances, chemicals. acetylcholine, catecholamines, endothelium I, angiotensin II are 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 antithrombotic/anticoagulant properties. The negative (of the same name) charge on the surface of endothelial cells and platelets causes their mutual repulsion, which counteracts the adhesion of platelets 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 in conditions of vascular damage, the endothelium realizes its prothrombotic/procoagulant potential. Proinflammatory cytokines and other inflammatory mediators can induce endothelial cells to produce substances that promote thrombosis/hypercoagulation. During vascular injury, the 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 vasospasm or vascular thrombosis, which, in particular, is observed in some forms of coronary heart disease. In addition, regional circulatory 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 released by activated platelets, and thus limits their involvement in the process of thrombus formation. The endothelium is capable of producing coagulants and anticoagulants, and adsorbing numerous anticoagulants from the blood plasma - heparin, proteins C and S.

When the endothelium is damaged, its surface turns from antithrombotic to prothrombotic. If the pro-adhesive surface of the subendothelial matrix is ​​exposed, its components - adhesive proteins (von Willebrand factor, collagen, fibronectin, thrombospondin, fibrinogen, etc.) are immediately involved in the process of formation of the primary (vascular-platelet) thrombus, and then hemocoagulation.

Biologically active substances produced by endothelial cells, primarily cytokines, can have a significant impact on metabolic processes through the endocrine type of action, in particular, change tissue tolerance to fatty acids and carbohydrates. In turn, disorders 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, be it 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 one or another cardiovascular disease, and on the other hand, this disease itself often aggravates endothelial damage.

An example of such a vicious circle (“circulus vitiosus”) can be the situation that is created in the conditions of the development of arterial hypertension. Prolonged exposure to increased blood pressure on the vascular wall can ultimately lead to endothelial dysfunction, as a result of which the tone of vascular smooth muscles will increase and the processes of vascular remodeling will be launched (see below), one of the manifestations of which is thickening of the media (the muscular layer of the vascular wall) and a corresponding decrease in the diameter of the vessel. The active participation of endothelial cells 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 (“closure”) of a vicious circle.

Endothelium and proliferative processes. Endothelial cells are capable of producing both stimulators 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 (dendothelialization) results in smooth muscle proliferation, which can be inhibited by restoration 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 most powerful inducer of interstitial collagen gene expression, under certain conditions is capable of inhibiting vascular proliferation by feedback mechanism.

Endothelial cells also produce a number of growth factors that can stimulate the proliferation of cells in the vascular wall: platelet-derived growth factor (PDGF; Platelet Derived Growth Factor), so named because it was first isolated from platelets, is an extremely potent mitogen that stimulates DNA synthesis and cell division; endothelial growth factor (EDGF; Endothelial-Cell-Derived Growth Factors), is capable, in particular, of stimulating 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 have shown 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: intermediary proteins or G-proteins, which control the coupling of cell surface receptors with effekgor 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 chemotactic molecules, 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, 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 use the enzyme lipoprotein lipase to convert triglycerides into free fatty acids. The released fatty acids then enter the subendothelial space, providing a source of energy for smooth muscle and other cells. Endothelial cells contain receptors for atherogenic low-density lipoproteins, which predetermines their participation in the development of atherosclerosis.