Damage to the vascular endothelium is a trigger for the development of atherosclerosis. Markers of endothelial dysfunction

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1. The development of atherosclerosis and its complications (ischemic heart disease, acute myocardial infarction, cerebral stroke, remodeling of the heart and blood vessels, heart failure, and, finally, death) is a sequential chain of events united by the concept of the cardiovascular continuum (CVC). The triggering point for SSC is a number of diseases and factors, such as arterial hypertension, lipid and carbohydrate metabolism disorders, smoking, etc. (so-called “risk factors”).

2. The influence of risk factors on the development of SSC can be carried out with the participation of various mechanisms. One of the most important among them is endothelial dysfunction (ED). ED is defined as the loss of endothelial barrier properties, the ability to regulate the tone and thickness of the vessel, control the processes of coagulation and fibrinolysis, and have an immune and anti-inflammatory effect. The underlying mechanisms of ED are associated with a decrease in the synthesis and increased breakdown of NO - a universal biological mediator that blocks vasoconstrictive, proliferative and aggregative effects provoked by risk factors. Hyperactivation of the renin-angiotensin-aldosterone system (RAAS) plays a key role in NO metabolism disorders and the development of ED. Increased synthesis of angiotensin II on the surface of endothelial cells leads not only to a decrease in the expression of NO, but also to an acceleration of the proliferation of SMCs (the development of hypertrophy of the vascular wall - HSS and left ventricle LVH), to increased adhesiveness and permeability of the vessel and the development of microangiopathy, increased inflammatory component of the reaction vascular wall on the impact of risk factors.

The loss of barrier qualities by the endothelium, increased permeability of the wall to cholesterol-rich lipoproteins and macrophages serves as the basis for the development of atherosclerotic changes (lipid spots, streaks, and then plaques) in the intima of the vessel. The gradual development of a chronic stenotic process in the coronary arteries of the coronary arteries and the subsequent hibernation of the myocardium themselves gradually lead to cardiac remodeling. This is also facilitated by the energy-intensive and hemodynamically (through an increase in peripheral vascular resistance) interconnected GSS and LVH.

A significant acceleration in the development of SSC occurs when an atherosclerotic plaque is destabilized and ruptured and a thrombus is formed at the site of rupture. The clinical expression of this situation is acute coronary syndrome (ACS) and AMI. (or stroke in relation to the brain). The main reason for the destabilization of the plaque and the development of ACS is ED: the development of inflammation on its surface, increasing the permeability of the endothelium to macrophages and blood cells, increasing the coagulating and weakening fibrinolytic properties of the blood.

Reducing the consequences of a vascular accident (AMI, stroke) and reducing the death of cardiomyocytes (CMC) is the main goal of the next stage of CVS. Achieving this goal became possible with the advent of drug and surgical methods for eliminating (preventing) stenosis. The most effective and affordable of them is angioplasty with stenting of target vessels. However, mechanical impact on the vessel and elimination of stenosis, especially in conditions of ED, after some time often provokes the development of restenosis, which can contribute to the formation of even more CMC and aggravate the course of the underlying disease. The same applies to reconstructive operations on the vessels of the heart (brain, etc.).

At the next stage of SSC - during post-infarction cardiac remodeling, the absence of the protective role of the vascular endothelium leads to the rapid development of clinically significant heart failure and, without appropriate treatment, to death. Proliferative processes in the myocardium with a predominance of fibrosis, a lack of reserve for dilatation of the microvascular bed as a consequence, a decrease in myocardial contractility, especially under load, is a direct result of ED. A manifestation of ED in the periphery in patients with CHF is a violation of microcirculation in the striated muscles and the associated decrease in stress tolerance, a tendency to edema, and the development of cachexia.

The central role of ED in the development of CVS is due to the fact that 90% of the RAAS components are located in tissues: in the heart, kidneys, adrenal glands, but mainly on the surface of vascular endothelial cells. Therefore, hyperactivation of the RAAS most often and quickly affects the vascular endothelium. Knowledge of the mechanisms and driving forces of the development of CVS arms us with the understanding that the optimal means of preventing and treating CVS diseases are, among others, measures to eliminate ED. Since hyperactivation in the tissue (endothelial) RAAS plays a key role in the development of ED, the most effective drugs will be ACE inhibitors. having the highest affinity for tissue components of the RAAS. The drug of choice among other ACE inhibitors is quinapril (Accupro), a drug with the best indicators of blocking activity of the tissue RAAS.

There is currently growing interest in the role of endothelial function in the pathogenesis of cardiovascular diseases.

The endothelium is a monolayer of endothelial cells that functions as a transport barrier between the blood and the vascular wall, responding to the mechanical effects of blood flow and tension in the vascular wall, and sensitive to various neurohumoral agents. The endothelium continuously produces a huge amount of biologically important active substances. It is essentially a giant paracrine organ in the human body. Its main role is determined by maintaining cardiovascular homeostasis by regulating the equilibrium state of the most important processes:

a) vascular tone (vasodilation/vasoconstriction);

b) hemovascular hemostasis (production of procoagulant/anticoagulant mediators);

c) cell proliferation (activation/inhibition of growth factors);

d) local inflammation (production of pro- and anti-inflammatory factors) (Table 1).

Among the abundance of biologically active substances produced by the endothelium, the most important is nitric oxide - NO. Nitric oxide is a powerful vasodilator; in addition, it is a mediator of the production of other biologically active substances in the endothelium; a short-lived agent whose effects appear only locally. Nitric oxide plays a key role in cardiovascular hemostasis not only due to the regulation vascular tone, but also inhibiting adhesion and aggregation of circulating platelets, preventing the proliferation of vascular smooth muscle cells, various oxidative and migratory processes of atherogenesis.

Table 1

Functions and mediators of the endothelium

	Endothelial mediators
Vasoregulatory (secretion of vasoactive mediators)	Vasodilators (NO, prostacyclin, bradykinin) Vasoconstrictors (endothelin-1, thromboxane A2, angiotensin II, endoperoxides)
Participation in hemostasis (secretion of coagulation factors and fibrinolysis)	Procoagulants (thrombin, plasminogen activator inhibitor) Anticoagulants (NO, prostacyclin, thrombomodulin, tissue plasminogen activator)
Regulation of proliferation	Secretion of endothelial growth factor, platelet-derived growth factor, fibroblast growth factor) Secretion of heparin-like growth inhibitors, NO
Regulation of inflammation	Secretion of adhesion factors, selectins Production of superoxide radicals
Enzyme activity	Secretion of protein kinase C, angiotensin-converting enzyme

Currently, endothelial dysfunction is defined as an imbalance of opposing mediators, the emergence of “vicious circles” that disrupt cardiovascular homeostasis. All major cardiovascular risk factors are associated with endothelial dysfunction: smoking, hypercholesterolemia, hypertension and diabetes. Disturbances in endothelial function appear to occupy one of the first places in the development of many cardiovascular diseases - hypertension, coronary artery disease, chronic heart failure, chronic renal failure. Endothelial dysfunction is the earliest stage in the development of atherosclerosis. Numerous prospective studies have shown the relationship between endothelial dysfunction and the development of adverse cardiovascular complications in patients with coronary artery disease, hypertension, and peripheral atherosclerosis. That is why the concept of the endothelium as a target organ for the prevention and treatment of cardiovascular diseases has now been formulated.

In patients with hypertension, endothelial dysfunction is manifested primarily by impaired endothelium-dependent vasodilation (EDVD) in arteries of various regions, including skin, muscle, renal and coronary arteries, and microvasculature. The mechanism for the development of endothelial dysfunction in hypertension is hemodynamic and oxidative stress, which damages endothelial cells and destroys the nitric oxide system.

Diagnosis of endothelial dysfunction

Methods for studying the function of the endothelium of peripheral arteries are based on assessing the ability of the endothelium to produce NO in response to pharmacological (acetylcholine, methacholine, bradykinin, histamine) or physical (changes in blood flow) stimuli, direct determination of the level of NO and other NO-dependent mediators, as well as on the assessment of “ surrogate" indicators of endothelial function. The following methods are used for this:

veno-occlusive plethysmography;

coronary angiography;

Magnetic resonance imaging;

ultrasonic duplex scanning peripheral arteries with testing;

assessment of microalbuminuria.

The most practical non-invasive method is duplex scanning of peripheral arteries, in particular assessing changes in the diameter of the brachial artery before and after short-term limb ischemia.

Methods for correcting endothelial dysfunction

Therapy for endothelial dysfunction is aimed at restoring the balance of the factors described above, limiting the action of some endothelial mediators, compensating for the deficiency of others and restoring their functional balance. In this regard, data on the influence of various medicines on the functional activity of the endothelium. The ability to influence NO-dependent vasodilation is shown for nitrates, ACE inhibitors, calcium antagonists, as well as for new beta-blockers latest generation, which have additional vasodilating properties.

Nebivolol is the first of the beta-blockers, the vasodilating effect of which is associated with the activation of the release of NO from the vascular endothelium. In comparative clinical studies this drug increased the vasodilating activity of the endothelium, while second-generation b-blockers (atenolol) did not affect vascular tone. When studying pharmacological properties nebivolol has been shown to be a racemic mixture of D- and L-isomers, with the D-isomer having a β-adrenergic blocking effect and the L-isomer stimulating NO production.

The combination of b-adrenergic receptor blockade and NO-dependent vasodilation provides not only the hypotensive effect of nebivolol, but also a beneficial effect on systolic and diastolic myocardial function. Early studies of the vasodilatory effects of nebivolol in healthy volunteers showed that, when administered acutely intravenously or intraarterially, it caused a dose-dependent vasodilation of arterial and venous vessels mediated through NO. The vasodilating effect of nebivolol was manifested in various regions of the vascular and microvasculature and was accompanied by an increase in arterial elasticity, which was also confirmed in patients with hypertension. Evidence for an NO-dependent mechanism for the vasodilating effect of nebivolol has been obtained not only in experimental studies, but also in clinical settings using tests with acetylcholine, an inhibitor of the arginine/NO system. Hemodynamic unloading of the myocardium provided by nebivolol reduces myocardial oxygen demand and increases cardiac output in patients with diastolic myocardial dysfunction and heart failure. It is the ability to modulate the reduced production of nitric oxide, which has angioprotective and vasodilating properties, that is the basis for the antiatherosclerotic effect of the drug.

IN modern research devoted to the study of the vasodilating effect of nebivolol in patients with hypertension, it was shown that nebivolol at a dose of 5 mg per day in comparison with bisoprolol at a dose of 10 mg or atenolol at a dose of 50 mg per day causes a significant decrease in the vascular resistance index, an increase in the cardiac index, an increase microvascular blood flow in various departments vascular bed, in the absence of differences in the degree of reduction in blood pressure and the absence of these effects in atenolol and bisoprolol.

Thus, nebivolol has clinically significant advantages over other beta-blockers. The presence of the NO-dependent vasodilating effect of nebivolol in patients with hypertension may be of great importance in terms of the protective role of nitric oxide against cardiovascular risk factors and especially the development of atherosclerosis. By restoring balance in the nitric oxide system, nebivolol can eliminate endothelial dysfunction in patients with hypertension both in the arterial and microvasculature and have an organoprotective effect, which was the goal of our study.

Study of the vasoprotective effect of nebivolol

A study of the vasoprotective effect of nebivolol in comparison with the ACE inhibitor quinapril was carried out in 60 patients with hypertension (average age 56 years). The vasoprotective effect was assessed by the dynamics of the vasodilating function of the endothelium using non-invasive vasodilation tests with reactive hyperemia (endothelium-dependent vasodilation) and nitroglycerin (endothelium-independent vasodilation) and the state of the intima-media complex of the wall of the carotid arteries in the bifurcation area.

Patients underwent a general clinical examination, assessment of office blood pressure and ABPM, duplex scanning of the carotid arteries with determination of the thickness of the intima-media complex (IMT), assessment of endothelium-dependent vasodilation (EDVD) and endothelium-independent vasodilation (ENIVD) during ultrasound examination of the brachial artery . An increase in arterial dilatation of 10% was taken as normal EDVD; an increase of more than 15% was taken as normal EDVD; in addition, the vasodilation index (VDI) was assessed - the ratio of the degree of increase in EDVD to the increase in EDVD (normal index 1.5-1.9). When assessing IMT, up to 1.0 mm was considered normal, 1.0-1.4 mm was considered thickening, and more than 1.4 mm was considered as the formation of an atherosclerotic plaque.

Data on “office” blood pressure after 6 months of treatment

nebivolol and quinapril

After 6 months of treatment, the decrease in SBP/DBP during nebivolol therapy was 17/12.2 mm Hg. Art., during therapy with quinapril – 19.2/9.2 mm Hg. Art. Nebivolol showed a more pronounced decrease in DBP levels: according to office measurements, DBP reached 86.8 versus 90 mm Hg. Art. (R

Analysis of the vasodilating function of the brachial artery

Initially, in patients with hypertension, significant disturbances in the vasodilating function of the brachial artery were observed, mainly in the form of a decrease in EDVD: a normal EDVD value in a test with reactive hyperemia (an increase in arterial diameter of more than 10%) was recorded in only one patient; 22 patients (36%) had normal initial indicators of EPVD in the nitroglycerin test (an increase in arterial diameter by more than 15%), while the IPV was 2.4 ± 0.2.

After 6 months of therapy, the diameter of the brachial artery at rest increased by 1.9% in the nebivolol group and by 1.55% in the quinapril group (p = 0.005), which is a manifestation of the vasodilating effect of the drugs. Improvement in vasodilating vascular function was noted to a greater extent due to EDVD: the increase in vessel diameter in the test with reactive hyperemia reached 12.5 and 10.1% during therapy with nebivolol and quinapril, respectively. The severity of the effect of nebivolol on EDVD was greater both in terms of the degree of increase in EDVD (p = 0.03) and in the frequency of normalization of EDVD indicators (in 20 patients (66.6%) versus 15 patients (50%) in the quinapril group). The improvement in ENVD was less pronounced: only 10% of patients showed an increase in vasodilation in a test with nitroglycerin in both groups (Fig. 1). IPV at the end of treatment was 1.35 ± 0.1 in the nebivolol group and 1.43 ± 0.1 in the quinapril group.

Results of studying the intima-madia complex of the carotid arteries

Initially, normal indices of the intima-media complex of the carotid arteries in the bifurcation area (IMT 1.4 mm).

After 6 months of treatment, the number of patients with atherosclerotic plaques did not change; the rest had a decrease in IMT by 0.06 mm (7.2%, p

When analyzing the correlation relationships between EDVD and EPVD and the level of initial “office” BP, a statistically significant negative correlation was revealed between the level of SBP and DBP and the degree of increase in EDVD and EDVD. This suggests that the higher the initial blood pressure level in patients with hypertension, the lower the ability of blood vessels to undergo normal vasodilation (Table 2). When analyzing the relationships between EDVD and ENVDP and the severity of the hypotensive effect by 6 months of therapy, a statistically significant negative correlation was revealed between the achieved level of DBP and the degree of increase in EDVD and ENVDP, indicating the role of normalization of DBP in ensuring the vasodilating function of blood vessels, and this dependence occurred only in relation to nebivolol and absent for quinapril.

table 2

Correlation analysis of the relationship between blood pressure and vasodilating vascular function

Indicators	n	Spearman	p
Increase in EDV and SBP office initially
Increase in EDV and DBP office initially
Increase in EPVD and office systolic blood pressure initially
Increase in EPVD and DBP office initially
Increase in EDV and office systolic blood pressure after 6 months
Increase in EPV and SBP office after 6 months
Increase in EDV and DBP office after 6 months
Increase in EPVD and DBP office after 6 months

Thus, our study showed that almost all patients with hypertension have endothelial dysfunction in the form of a slow and insufficient vasodilating effect during a test with reactive hyperemia, which indicates impaired EDVD, with a slight decrease in EDVD (in one third of patients, EDVD remained normal ), which correlated with the degree of increase in blood pressure. As a result of treatment, more pronounced changes in vasodilatory vascular function were observed in the nebivolol group, predominantly EDVD, which may indicate the presence of NO-dependent mechanisms of action in the drug. In addition, the effect on endothelial function was accompanied by a more pronounced hypothesized effect of nebivolol, especially on the level of DBP, which is additional confirmation of the vasodilating effect of this b-blocker. By normalizing endothelial function, nebivolol reduced IMT in patients with hypertension and helped inhibit the progression of atherosclerotic plaques. This effect of nebivolol was comparable to the most highly lipophilic and tissue-specific ACE inhibitor, quinapril, whose antiatherogenic properties were shown in the large QUIET study.

Study of the nephroprotective effect of nebivolol

Endothelial dysfunction is the triggering pathogenetic mechanism for the development of nephropathy in patients with hypertension. An increase in systemic blood pressure and disruption of intraglomerular hemodynamics, damaging the endothelium of glomerular vessels, increases the filtration of proteins through the basement membrane, which in the early stages is manifested by microproteinuria, and later by the development of hypertensive nephroangiosclerosis and chronic renal failure. The most significant mediators of the development of nephroangiosclerosis are angiotensin II and an inferior precursor of NO - abnormal dimethylarginine, which contributes to the development of deficiency in the formation of nitric oxide. Therefore, restoration of the function of glomerular endothelial cells may provide a nephroprotective effect against the background of antihypertensive therapy. In this regard, we studied the possibilities of the effect of nebivolol on microproteinuria in 40 patients with hypertension (average age 49.2 years) in comparison with quinapril.

According to office blood pressure measurements, the hypotensive effect of nebivolol and quinapril after 6 months of therapy was comparable: 138/85 and 142/86 mmHg. st respectively. However, achievement of the target blood pressure level by the end of treatment was observed in 41% of patients receiving nebivolol, and only in 24% of patients receiving quinapril, and the addition of HCTZ was required in 6 and 47% of cases, respectively.

Initially, microproteinuria was detected in 71% of patients with hypertension, and in these patients the blood pressure level was significantly higher than in patients without microproteinuria. During treatment with nebivolol and quinapril, a decrease in albumin excretion was observed to normal indicators both in daily and morning portions of urine; the level of b2-microglobulin excretion remained elevated throughout the treatment period in both groups (Fig. 2).

Thus, both drugs effectively improved glomerular filtration and, as a result, reduced albuminuria in patients with hypertension. It is known that the mechanism of the nephroprotective effect of the ACE inhibitor quinapril is the elimination of the damaging effect of angiotensin II; for nebivolol, which does not have a direct effect on angiotensin II, the nephroprotective effect is realized only through a direct vasodilating effect through the NO system.

Conclusion

Nebivolol, a representative of a new generation of b-blockers with a vasodilating effect, belongs to the class of modern vasoactive drugs that regulate endothelial function through the NO system. Nebivolol showed pronounced organoprotective properties in patients with hypertension. Considering clinical significance endothelial dysfunction in the development of cardiovascular diseases, nebivolol may be an alternative to ACE inhibitors.

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... "a person's health is determined by the health of his blood vessels."

Endothelium is a single-layer layer of specialized cells of mesenchymal origin that line blood vessels, lymphatic vessels and the cavities of the heart.

Endothelial cells lining blood vessels have an amazing ability change its number and location in accordance with local requirements. Almost all tissues need blood supply, and this in turn depends on endothelial cells. These cells create a life support system capable of flexible adaptation with ramifications in all areas of the body. Without this ability of endothelial cells to expand and repair the network of blood vessels, tissue growth and healing processes would not be possible.

Endothelial cells line the entire vascular system- from the heart to the smallest capillaries - and control the transition of substances from tissues to blood and back. Moreover, studies of embryos have shown that the arteries and veins themselves develop from simple small vessels built exclusively from endothelial cells and a basement membrane: connective tissue and smooth muscle where needed are added later under the influence of signals from endothelial cells.

In a form familiar to human consciousness The endothelium is an organ weighing 1.5-1.8 kg (comparable to the weight of, for example, 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 separating 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.

Histology. The endothelium morphologically resembles single-layer squamous epithelium and calm state appears to be a layer consisting of individual cells. In their shape, endothelial cells look like very thin plates irregular shape and various lengths. Along with elongated, spindle-shaped cells, you can often see cells with rounded ends. The nucleus is located in the central part of the endothelial cell oval shape. Typically, most cells have one nucleus. In addition, there are cells that do not have a nucleus. It disintegrates in protoplasm, just as it occurs in erythrocytes. These anucleate cells undoubtedly represent dying cells that have completed their life cycle. In the protoplasm of endothelial cells one can see all the typical inclusions (Golgi apparatus, chondriosomes, small lipoid grains, sometimes pigment grains, etc.). At the moment of contraction, the finest fibrils very often appear in the protoplasm of the cells, forming in the exoplasmic layer and very reminiscent of the myofibrils of smooth muscle cells. The connection of endothelial cells with each other and the formation of a layer by them served as the basis for comparing the vascular endothelium with the real epithelium, which, however, is incorrect. The epithelioid arrangement of endothelial cells is preserved only under normal conditions; with various irritations, the cells sharply change their character and take on the appearance of cells that are almost completely indistinguishable from fibroblasts. In their epithelioid state, the bodies of endothelial cells are syncytially connected by short processes, which are often visible in the basal part of the cells. On the free surface they probably have a thin layer of exoplasm that forms integumentary plates. Many studies suggest that a special cementing substance is secreted between endothelial cells, which glues the cells together. Behind last years Interesting data have been obtained allowing us to assume that the easy permeability of the endothelial wall of small vessels depends precisely on the properties of this substance. Such indications are very valuable, but they need further confirmation. By studying the fate and transformations of the excited endothelium, we can come to the conclusion that in various vessels Endothelial cells are at various stages of differentiation. Thus, the endothelium of the sinus capillaries of the hematopoietic organs is directly connected with the reticular tissue surrounding it and, in its abilities for further transformations, does not differ noticeably from the cells of this latter - in other words, the described endothelium is little differentiated and has some potencies. The endothelium of large vessels consists, in all likelihood, of more highly specialized cells that have lost the ability to undergo any transformations, and therefore it can be compared with fibrocytes of connective tissue.

The endothelium is not a passive barrier between blood and tissues, but an active organ, dysfunction of which is an essential component of the pathogenesis of almost all cardiovascular diseases, including atherosclerosis, hypertension, coronary heart disease, chronic heart failure, and is also involved in inflammatory reactions and autoimmune processes , diabetes, thrombosis, sepsis, growth of malignant tumors, etc.

Main functions of the vascular endothelium:
release of vasoactive agents: nitric oxide (NO), endothelin, angiotensin I-AI (and possibly angiotensin II-AII, prostacyclin, thromboxane
obstruction of coagulation (blood clotting) and participation in fibrinolysis- thromboresistant surface of the endothelium (the same charge on the surface of the endothelium and platelets prevents the “sticking” - adhesion - of platelets to the vessel wall; the formation of prostacyclin, NO (natural disaggregants) and the formation of t-PA (tissue plasminogen activator) also prevents coagulation; expression on the surface of endothelial cells thrombomodulin - a protein capable of binding thrombin and heparin-like glycosaminoglycans
immune functions- presentation of antigens to immunocompetent cells; secretion of interleukin-I (T-lymphocyte stimulator)
enzymatic activity- expression on the surface of endothelial cells of the angiotensin-converting enzyme - ACE (conversion of AI to AII)
participation in the regulation of smooth muscle cell growth through secretion of endothelial growth factor and heparin-like growth inhibitors
protection of smooth muscle cells from vasoconstrictor effects

Endocrine activity of the endothelium depends on him functional state, which is largely determined by the incoming information perceived by him. The endothelium contains numerous receptors for various biologically active substances; it also perceives the pressure and volume of moving blood - the so-called shear stress, which stimulates the synthesis of anticoagulants and vasodilators. Therefore, the greater the pressure and speed of moving blood (arteries), the less often blood clots form.

Stimulates the secretory activity of the endothelium:
change in blood flow speed, such as increased blood pressure
release of neurohormones- catecholamines, vasopressin, acetylcholine, bradykinin, adenosine, histamine, etc.
factors released from platelets during their activation– serotonin, ADP, thrombin

The sensitivity of endothelial cells to blood flow speed, expressed in their release of a factor that relaxes vascular smooth muscles, leading to an increase in the lumen of the arteries, was found in all studied main arteries of mammals, including humans. The relaxation factor secreted by the endothelium in response to a mechanical stimulus is a highly labile substance that is not fundamentally different in its properties from the mediator of endothelium-dependent dilator reactions caused by pharmacological substances. The latter position asserts the “chemical” nature of signal transmission from endothelial cells to vascular smooth muscle formations during the dilator reaction of arteries in response to an increase in blood flow. Thus, the arteries continuously regulate their lumen according to the speed of blood flow through them, which ensures stabilization of pressure in the arteries in the physiological range of changes in blood flow values. This phenomenon is of great importance in conditions of the development of working hyperemia of organs and tissues, when there is a significant increase in blood flow; with increased blood viscosity, causing growth resistance to blood flow in the vascular network. In these situations, the mechanism of endothelial vasodilation can compensate for an excessive increase in resistance to blood flow, leading to a decrease in blood supply to tissues, an increase in the load on the heart and a decrease in cardiac output. It has been suggested that damage to the mechanosensitivity of vascular endothelial cells may be one of the etiological (pathogenetic) factors in the development of obliterating endarteritis and hypertension.

Endothelial dysfunction, which occurs when exposed to damaging agents (mechanical, infectious, metabolic, immune complex, etc.), sharply changes the direction of its endocrine activity to the opposite: vasoconstrictors and coagulants are formed.

Biologically active substances produced by the endothelium, act mainly paracrine (on neighboring cells) and autocrine-paracrine (on the endothelium), but the vascular wall is a dynamic structure. Its endothelium is constantly renewed, obsolete fragments, together with biologically active substances, enter the blood, spread throughout the body and can affect the systemic blood flow. The activity of the endothelium can be judged by the content of its biologically active substances in the blood.

Substances synthesized by endothelial cells can be divided into the following groups:
factors regulating vascular smooth muscle tone:
- constrictors- endothelin, angiotensin II, thromboxane A2
- dilators- nitric oxide, prostacyclin, endothelial depolarizing factor
hemostasis factors:
- antithrombogenic- nitric oxide, tissue plasminogen activator, prostacyclin
- prothrombogenic- platelet-derived growth factor, plasminogen activator inhibitor, von Willebrand factor, angiotensin IV, endothelin-1
factors affecting cell growth and proliferation:
- stimulants- endothelin-1, angiotensin II
- inhibitors- prostacyclin
factors influencing inflammation- tumor necrosis factor, superoxide radicals

Normally, in response to stimulation, the endothelium reacts by increasing the synthesis of substances that cause relaxation of smooth muscle cells of the vascular wall, primarily nitric oxide.

!!! the main vasodilator that prevents tonic contraction of vessels of neuronal, endocrine or local origin is NO

Mechanism of action NO. NO is the main stimulator of cGMP formation. By increasing the amount of cGMP, it reduces the calcium content in platelets and smooth muscles. Calcium ions are obligatory participants in all phases of hemostasis and muscle contraction. cGMP, activating cGMP-dependent proteinase, creates conditions for the opening of numerous potassium and calcium channels. A particularly important role is played by proteins – K-Ca channels. The opening of these channels for potassium leads to relaxation of smooth muscles due to the release of potassium and calcium from the muscles during repolarization (attenuation of the biocurrent of action). Activation of K-Ca channels, the density of which on membranes is very high, is the main mechanism of action of nitric oxide. Therefore, the final effect of NO is antiaggregating, anticoagulant and vasodilatory. NO also prevents the growth and migration of vascular smooth muscles, inhibits the production of adhesive molecules, and prevents the development of spasm in blood vessels. Nitric oxide functions as a neurotransmitter, a translator of nerve impulses, is involved in memory mechanisms, and provides a bactericidal effect. The main stimulator of nitric oxide activity is shear stress. The formation of NO also increases under the influence of acetylcholine, kinins, serotonin, catecholamines, etc. With intact endothelium, many vasodilators (histamine, bradykinin, acetylcholine, etc.) have a vasodilatory effect through nitric oxide. NO expands especially strongly cerebral vessels. If endothelial function is impaired, acetylcholine causes either a weakened or perverted response. Therefore, the vascular response to acetylcholine is an indicator of the state of the vascular endothelium and is used as a test of its functional state. Nitric oxide is easily oxidized, turning into peroxynitrate - ONOO-. This very active oxidative radical, which promotes the oxidation of low-density lipids, has cytotoxic and immunogenic effects, damages DNA, causes mutation, inhibits enzyme functions, and can destroy cell membranes. Peroxynitrate is formed during stress, lipid metabolism disorders, and severe injuries. High doses ONOO- enhance the damaging effects of free radical oxidation products. The decrease in nitric oxide levels occurs under the influence of glucocorticoids, which suppress the activity of nitric oxide synthase. Angiotensin II is the main antagonist of NO, promoting the conversion of nitric oxide to peroxynitrate. Consequently, the state of the endothelium establishes a relationship between nitric oxide (antiplatelet agent, anticoagulant, vasodilator) and peroxynitrate, which increases the level of oxidative stress, which leads to severe consequences.

Currently, endothelial dysfunction is understood as- imbalance between mediators that normally ensure the optimal course of all endothelium-dependent processes.

Functional restructuring of the endothelium under the influence of pathological factors goes through several stages:
first stage – increased synthetic activity of endothelial cells
the second stage is a violation of the balanced secretion of factors regulating vascular tone, the hemostasis system, and the processes of intercellular interaction; at this stage, the natural barrier function of the endothelium is disrupted and its permeability to various plasma components increases.
the third stage is endothelial depletion, accompanied by cell death and slow endothelial regeneration processes.

As long as the endothelium is intact and not damaged, it synthesizes mainly anticoagulation factors, which are also vasodilators. These biologically active substances prevent the growth of smooth muscles - the walls of the vessel do not thicken, and its diameter does not change. In addition, the endothelium adsorbs numerous anticoagulant substances from blood plasma. The combination of anticoagulants and vasodilators on the endothelium under physiological conditions is the basis for adequate blood flow, especially in microcirculation vessels.

Damage to the vascular endothelium and exposure of the subendothelial layers triggers aggregation and coagulation reactions that prevent blood loss and causes vascular spasm, which can be very strong and is not eliminated by denervation of the vessel. The formation of antiplatelet agents stops. At short-term action damaging agents, the endothelium continues to perform protective function, preventing blood loss. But with prolonged damage to the endothelium, according to many researchers, the endothelium begins to play a key role in the pathogenesis of a number of systemic pathologies (atherosclerosis, hypertension, strokes, heart attacks, pulmonary hypertension, heart failure, dilated cardiomyopathy, obesity, hyperlipidemia, diabetes mellitus, hyperhomocysteinemia, etc. ). This is explained by the participation of the endothelium in the activation of the renin-angiotensin and sympathetic systems, the switching of endothelial activity to the synthesis of oxidants, vasoconstrictors, aggregates and thrombogenic factors, as well as a decrease in the deactivation of endothelial biologically active substances due to damage to the endothelium of some vascular areas (in particular, in the lungs) . This is facilitated by such modifiable risk factors for cardiovascular diseases as smoking, hypokinesia, salt load, various intoxications, disorders of carbohydrate, lipid, protein metabolism, infection, etc.

Doctors, as a rule, encounter patients in whom the consequences of endothelial dysfunction have already become symptoms of cardiovascular diseases. Rational therapy should be aimed at eliminating these symptoms (clinical manifestations of endothelial dysfunction may include vasospasm and thrombosis). Treatment of endothelial dysfunction is aimed at restoring the vascular dilator response.

Drugs that have the potential to affect endothelial function can be divided into four main categories:
replacing natural projective endothelial substances- stable PGI2 analogues, nitrovasodilators, r-tPA
inhibitors or antagonists of endothelial constrictor factors- angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, TxA2 synthetase inhibitors and TxP2 receptor antagonists
cytoprotective substances: free radical scavengers superoxide dismutase and probucol, lazaroid inhibitor of free radical production
lipid-lowering drugs

Recently installed important role of magnesium in the development of endothelial dysfunction. It has been shown that administration of magnesium preparations can significantly improve (almost 3.5 times more than placebo) endothelium-dependent dilatation of the brachial artery after 6 months. At the same time, a direct linear correlation was also revealed - the dependence between the degree of endothelium-dependent vasodilation and the concentration of intracellular magnesium. One possible mechanism explaining the beneficial effects of magnesium on endothelial function may be its antiatherogenic potential.

Valvachev A.A. Moscow

Endothelium produces a wide range of biological active substances of the variable functional spectrum, including regulators of regional circulation. Endothelial dysfunction can initiate (or modulate) a number of pathological conditions (e.g. atherosclerosis, hypertension, stroke, myocardial infarction, etc.).

Research over the past 10-15 years has significantly changed the understanding on the role of vascular endothelium in general homeostasis. It turned out that the endothelium synthesizes a huge amount of biologically active substances (BAS), which play a very important role in many processes in health and disease (hemodynamics, hemostasis, immune reactions, regeneration, etc.). The presence of such extensive endocrine activity in the endothelium gave rise to D. Antomuoci, L.A. Fitzpatrick (1996) call it the endocrine tree.

In this review we will focus on only one direction endothelial functioning- its participation in the formation of adequate blood flow, which is ensured by the coordination of the aggregative state of the blood and the tone (diameter) of blood vessels.

The endocrine activity of the endothelium depends on its functional state, which is largely determined by the incoming information it perceives. The endothelium contains numerous receptors for various biologically active substances (BAS); it also perceives the pressure and volume of moving blood - the so-called shear stress, which stimulates the synthesis of anticoagulants and vasodilators. Therefore, the greater the pressure and speed of moving blood (arteries), the less often blood clots form.

Endothelial dysfunction, which occurs when exposed to damaging agents (mechanical, infectious, metabolic, immune complex, etc.), sharply changes the direction of its endocrine activity to the opposite: vasoconstrictors and coagulants are formed.

Biologically active substances produced by the endothelium act mainly paracrine (on neighboring cells) and autocrine-paracrine (on the endothelium), but the vascular wall is a dynamic structure. Its endothelium is constantly renewed, obsolete fragments, together with biologically active substances, enter the blood, spread throughout the body and can affect the systemic blood flow. The activity of the endothelium can be judged by the content of its biologically active substances in the blood.

The structure of the vascular wall creates a certain pattern in the distribution of coagulation factors (vasoconstrictors) and anticoagulation factors (vasodilators). While the endothelium is intact and not damaged, it synthesizes mainly anticoagulation factors, which are also vasodilators. These biologically active substances prevent the growth of smooth muscles - the walls of the vessel do not thicken, and its diameter does not change. In addition, the endothelium adsorbs numerous anticoagulant substances from blood plasma. The combination of anticoagulants and vasodilators on the endothelium under physiological conditions is the basis for adequate blood flow, especially in microcirculation vessels.

Damage to the vascular endothelium and exposure of the subendothelial layers triggers aggregation and coagulation reactions that prevent blood loss, causes vascular spasm, which can be very strong and is not eliminated by denervation of the vessel (I.V. Davydovsky, 1969). The formation of antiplatelet agents stops. During short-term exposure to damaging agents, the endothelium continues to perform a protective function, preventing blood loss. But with prolonged damage to the endothelium, according to many researchers, the endothelium begins to play a key role in the pathogenesis of a number of systemic pathologies (atherosclerosis, hypertension, strokes, heart attacks, etc.). This is explained by the participation of the endothelium in the activation of the renin-angiotensin and sympathetic systems, the switching of endothelial activity to the synthesis of oxidants, vasoconstrictors, aggregates and thrombogenic factors, as well as a decrease in the deactivation of endothelial biologically active substances due to damage to the endothelium of some vascular areas (in particular, in the lungs) .

So, the endothelium can produce both coagulation factors (vasoconstrictors) and anticoagulation factors (vasodilators).

Endothelial activity under physiological conditions. Under physiological conditions, anticoagulants predominate on the inside of the vascular wall - their abundance and high activity ensure the reliability of the reaction.

The endothelium creates smooth surface, covered with mucous<дымкой>- glycocalyx - glycoproteins with anti-adhesive properties (prevent platelet adhesion). A small layer of fibrin covering the endothelium binds thrombin. The charge of the vessel wall is positive, which also prevents platelets (which have a positive charge) from approaching the endothelium. However, the main reason for the anticoagulant and vasodilator function of the vascular wall is the synthesis by the endothelium of the corresponding biologically active substances.

Nitric oxide. Great importance in maintaining adequate blood flow is due to nitric oxide (NO), which is synthesized by the endothelium and is a signaling molecule in the cardiovascular system - the vascular response is determined by the degree of NO formation. It occurs with the participation of NO synthase, which converts a-arginine into nitric oxide (NO), an unstable hormone with a half-life of several seconds. There are three isomers of the synthase:

I - neuronal (in nerve cells);
II - inducible (in macrophages);
III - endothelial (in the endothelium).

Mechanism of action NO. NO is the main stimulator of cGMP formation. By increasing the amount of cGMP, it reduces the calcium content in platelets and smooth muscles. Calcium ions are obligatory participants in all phases of hemostasis and muscle contraction. CGMP, activating cGMP-dependent proteinase, creates conditions for the opening of numerous potassium and calcium channels. A particularly important role is played by proteins - K Ca 2+ channels. The opening of these channels for potassium leads to relaxation of smooth muscles due to the release of potassium and calcium from the muscles during repolarization (attenuation of the biocurrent of action). Activation of K Ca 2+ channels, the density of which on membranes is very high, is the main mechanism of action of nitric oxide. Therefore, the final effect of NO is antiaggregating, anticoagulant and vasodilatory. NO also prevents the growth and migration of vascular smooth muscles, inhibits the production of adhesive molecules, and prevents the development of spasm in blood vessels. Nitric oxide functions as a neurotransmitter, a translator of nerve impulses, is involved in memory mechanisms, and provides a bactericidal effect.

The main stimulator of nitric oxide activity is shear stress. The formation of NO also increases under the influence of acetylcholine, kinins, serotonin, catecholamines, etc. With intact endothelium, many vasodilators (histamine, bradykinin, acetylcholine, etc.) have a vasodilatory effect through nitric oxide. NO dilates cerebral vessels especially strongly.

If endothelial function is impaired, acetylcholine causes either a weakened or perverted response. Therefore, the vascular response to acetylcholine is an indicator of the state of the vascular endothelium and is used as a test of its functional state (O.V. Ivanova et al., 1998).

Nitric oxide is easily oxidized, turning into peroxynitrate - ONOO-. This very active oxidative radical, which promotes the oxidation of low-density lipids (LDL), has cytotoxic and immunogenic effects, damages DNA, causes mutation, suppresses enzyme functions (T. Nguyen, Brunson, 1992), and can destroy cell membranes. Peroxynitrate is formed during stress, lipid metabolism disorders, and severe injuries. High doses of ONOO- enhance the damaging effects of free radical oxidation products. The decrease in nitric oxide levels occurs under the influence of glucocorticoids, which suppress the activity of nitric oxide synthase. Angiotensin II is the main antagonist of NO, promoting the conversion of nitric oxide to peroxynitrate.

Consequently, the state of the endothelium establishes a relationship between nitric oxide (antiplatelet agent, anticoagulant, vasodilator) and peroxynitrate, which increases the level of oxidative stress, which leads to severe consequences.

Prostacyclin. Another powerful anticoagulant, prostacyclin (prostaglandin Pgl 2), also plays a major role in hemostasis and hemodynamics. It is formed from phospholipids. Under the action of cyclooxygenase, arachidonic acid is cleaved, which is then converted into prostaglandins (Pg 2 and PgH 2) - unstable compounds. From them, under the action of the enzyme prostacyclin synthetase, prostacyclin is formed. The latter, acting on the smooth muscle membrane, includes type II messengers - adenylate cyclase, which increases the content of cAMP in the cell, which reduces the level of Ca 2+ in them.

Thus, prostacyclin acts as an antiplatelet agent, an anticoagulant factor, and the mechanism of action is the same as that of nitric oxide: the removal of calcium ions from smooth muscles, which prevents vasospasm, platelet aggregation and blood clotting. Prostacyclin and nitric oxide normalize lipid metabolism, preventing the development of atherosclerosis, and inhibit the growth process.

The stimulators of prostacyclin formation are, as for nitric oxide, shear stress, kinins and, unlike nitric oxide, angiothesin I.

Thrombomodulin. The vascular endothelium synthesizes a single-chain glycoprotein - thrombomodulin, which functions as a thrombin receptor. Thrombomodulin determines the speed and direction of the hemostasis process. Thrombin, having joined thrombomodulin, acquires new qualities: together with the anticoagulant proteins C and S (protein S cofactor), it forms an antiplatelet and antithrombotic complex, which prevents coagulation and inhibits fibrinolysis.

Proteins C and S are formed in the liver with the participation of vitamin K (protein S is also synthesized in the endothelium and megakaryocytes).

So, the vascular endothelium, through the thrombomodulin receptor, blocks the most active coagulation factor - thrombin.

The endothelium in a physiological state inactivates coagulation processes through other mechanisms. One of them is the synthesis of antithrombin III (also formed in the liver), a very strong activator of heparin, adsorbed by the endothelium from the blood. Heparin is produced in the liver, lungs, basophils, and mast cells. The endothelium itself synthesizes heparin-like substances.

Thus, under normal physiological conditions, the vascular endothelium prevents aggregation, blood coagulation and vasospasm, synthesizing a group of active substances: nitric oxide, prostacyclin, antithrombin III, etc. In addition, the endothelium, forming thrombomodulin, blocks active coagulants secreted by the liver and located in blood plasma (thrombin). And finally, the endothelium adsorbs anticoagulants from the blood plasma, preventing the adhesion and aggregation of platelets on its surface (heparin, proteins C and S).

Damage to the vascular wall or dysfunction of the endothelium. When damaged, the endothelium initiates blood clotting and vasoconstriction (spasm). Normally this is - defensive reaction, protecting the body from blood loss. But in other, pathological situations, this direction of endothelial activity begins or aggravates the pathological process.

The predominance of aggregates (and vasoconstrictors) is explained by the following main reasons. First, damage or dysfunction of the endothelium suppresses the secretion of antiaggregating, anticoagulant, and vasodilatory substances; secondly, the endothelium under these conditions secretes very active aggregates, coagulants and vasoconstrictors.

Endothelins is a group of polypeptides consisting of three isomers (endothelin-1, endothelin-2 and endothelin-3), differing in some variations and sequence of amino acids. The discovery of endothelins in 1988 made it possible to explain a number of unclear phenomena of hemostasis in health and disease.

The endothelium secretes<большой>endothelin<проэндотелин>(38 amino acid residues). Under the influence of the endothelin-converting enzyme located inside and on the surface of the endothelium, three endothelin isomers are formed from large endothelin.

Endothelins are bicyclic polypeptides consisting of 21 amino acid residues with two bisulfide bonds. There is a great similarity between the structure of endothelins and some neurotoxic peptides (scorpion and burrowing snake venoms).

With paracrine-autocrine action (i.e. on the endothelium), in response to vasoconstrictors, the endothelium produces antiplatelet agents, vasodilators (NO, prostacyclin) and natriuretic peptide.

The main mechanism of action of endothelins is the release of calcium, which causes:

1) stimulation of all phases of hemostasis, starting with platelet aggregation and ending with the formation of a red blood clot;

2) contraction and growth of vascular smooth muscles, leading to thickening of the vascular wall and a decrease in their diameter - vasoconstriction.

The synthesis of endothelins is enhanced by thrombin (which activates endothelin-converting enzyme) and platelets. Endothelins, in turn, cause platelet adhesion and aggregation.

The effects of endothelins are ambiguous and are determined by a number of reasons. The most active isomer is endothelin-1. It is formed not only in the endothelium, but also in vascular smooth muscles, neurons, glia, mesengial cells of the kidneys, liver and other organs. The half-life is 10-20 minutes, in blood plasma - 4-7 minutes. The lungs remove up to 90% of endothelins. Endothelin-1 has been implicated in a number of pathological processes(myocardial infarction, cardiac arrhythmia, pulmonary and systemic hypertension, atherosclerosis, etc.).

The effects of endothelins are also determined by the properties of the receptors with which endothelins bind. By binding to endothelin A receptors, they inhibit the synthesis of NO in blood vessels and cause vasoconstriction; By joining the B-1 receptors, they cause vasodilation (the formation of cAMP is inhibited and the synthesis of NO is enhanced).

The dose of endothelins also matters: under physiological conditions, endothelins are also formed, but in small quantities. Reacting with B-1 receptors, they dilate blood vessels. However, damaged endothelium synthesizes large amounts of endothelins, which cause vasoconstriction. Large doses of endothelins administered to volunteers lead to significant changes in systemic hemodynamics: a decrease in heart rate and stroke volume, an increase in vascular resistance in the systemic circulation by 50% and in the pulmonary circulation by 130%.

During bicycle ergometric exercise in athletes, the content of endothelin-3 in the blood very quickly increased with a simultaneous increase in the level of norepinephrine (S. Moeda et al., 1997). It is believed that the release of endothelins in this case is of a neurogenic nature.

The action of endothelins is specific in various vascular areas. They are destroyed in the lungs, but with pulmonary hypertension in the blood of the lungs, the level of these substances increases 2-3 times. Many endothelins are produced in the kidneys. Endothelins are believed to be involved in the development of renal hypertension. During strokes, their levels also increase in the cerebrospinal fluid.

Renin-angiotensin system. The vascular endothelium participates in the formation of a very active aggregating and vasoconstrictor system - the angiotensin system. The active form of this system is angiothesin-II, an octapeptide that causes a generalized and very strong (50 times stronger than adrenaline) reaction (V.F. Mordvin et al., 2001). The half-life of angiotensin-II is 10-12 minutes.

The mechanism of angiotensin II formation. The starting material for the synthesis of angiotensin II is angiotensinogen (β2-globulin), produced in the liver. Renin, synthesized in the juxtaglomerular apparatus of the kidneys, converts angiotensinogen into a low-active substance - angiotensin I.

The release of renin is stimulated by local (impaired blood circulation in the kidneys, kidney hypoxia) and systemic factors (decreased volume of circulating blood and water in the body, decreased blood pressure).

Angiotensin I is converted into the active substance - angiotensin II under the influence of angiotensin-converting enzyme (ACE), produced mainly by the vascular endothelium. Especially a lot of ACE is synthesized in the lungs, where there is a rich vascular network.

Since ACE inhibitors do not lead to complete blockade of angiotensin II, it is believed (Yu.V. Belousov, 2001) that there are other ways of converting angiotensin I into angiotensin II.

There are multi-level positive connections between the renin-angiotensin system and the sympathoadrenal system (SAS) (Zh.D. Kovaleva, 2001): angeotensin II activates the SAS, facilitates the release of norepinephrine, and the SAS, in turn, stimulates the formation of renin by the kidneys.

The effects of angiotensin II on organs are carried out through specific receptors of two types, present in many organs. The range of effects of angiotensin is very wide.

Together with SAS, angiotensin II causes:

Increased vascular tone (contraction of vascular smooth muscles);

An increase in the volume of circulating blood, which occurs due to the activation of the release of aldosterone (increasing sodium reabsorption) and increased secretion of ADH (retaining water in the body);

Positive tropic effects on the myocardium, leading to an increase in cardiac output;

Increasing the level of tissue plasminogen activator inhibitor (M.Ya. Kogan-Ponomarev, A.D. Dobrovolsky, 1996).

As a result, under the influence of angiotensin II, blood pressure increases.

With significant disturbances in the function and structure of the endothelium, a sharp activation of the renin-angiotensin system occurs, which makes it a damaging agent. This direction of action of the renin-angiotensin system is exacerbated by the close interaction of angiotensin II with the SAS - created vicious circle: the higher the activity of one system, the higher, accordingly, the other.

In large doses, angiotensin II contributes to the occurrence of oxidative (oxidative) stress, since, firstly, it inhibits the inactivation of norepinephrine by the lungs; secondly, it increases the activity of NAD- and NADP-dependent oxidase and converts nitric oxide into nitric superoxide - one of the main oxidizers of LDL; thirdly, it reduces NO synthesis by destroying bradykinin, a strong stimulator of NO formation; fourthly, it stimulates the oxidation of LDL by macrophages.

Thus, angiotensin II, connecting many factors affecting vascular tone (renin-angiotensin, kinin, sympathetic nervous system, aldosterone, etc.), becomes the central link in the regulation of blood pressure. Therefore, from a modern point of view, it is considered appropriate to use ACE inhibitors and angiotensin II receptor blockers in the treatment of patients with arterial hypertension, circulatory failure and the prevention of acute infarction.

In addition to the biologically active substances listed above, the endothelium produces a large number of vasoactive factors involved in hemostasis.

An important role is assigned fibronectin- a glycoprotein consisting of two chains connected by disulfide bonds. It is produced by all cells of the vascular wall, platelets. Fibronectin is a receptor for fibrin-stabilizing factor. Promotes platelet adhesion by participating in the formation of a white blood clot; binds heparin. By joining fibrin, fibronectin thickens the blood clot. Under the influence of fibronectin, smooth muscle cells, epithelial cells, and fibroblasts increase their sensitivity to growth factors, which can cause thickening of the muscular wall of blood vessels (narrowing of diameter).

Von Willebrand factor (VIII - vWF)- synthesized in endothelium and megakaryocytes; sulfated glycoprotein with high molecular weight (1000 cD); stimulates the onset of thrombus formation: promotes the attachment of platelet receptors to collagen and fibronectin of blood vessels, as well as to each other, i.e. enhances platelet adhesion and aggregation. Synthesis and isolation f. Von Willebrand increases under the influence of vasopressin, with damage to the endothelium. Since all stress conditions increase the release of vasopressin, under stress and extreme conditions the thrombogenicity of blood vessels increases, which is facilitated by an increase in the synthesis of f. Von Willebrand.

VIII-vWF is also a carrier of f. VIII - antihemophilic globulin A, a protein with a lower molecular weight (200 kDa). F.VIII is produced in the liver and by macrophages and is involved in the process of the internal cascade of fibrin formation.

F. Willebrand healthy people prevents the growth of blood clots in blood vessels by activating the formation of plasmin.

Thromboxane A 2 (TxA 2) - a very active factor - promotes rapid platelet aggregation, increases the availability of their receptors for fibrinogen, activates coagulation, constricts blood vessels, and causes bronchospasm. TxA 2 is produced by vascular smooth muscles and platelets. One of the factors that stimulates the release of thromboxane A2 is calcium, which is released in large quantities from platelets at the beginning of their aggregation. Thromboxane further increases the calcium content in the cytoplasm of platelets. Calcium activates phospholipase A2, which converts arachidonic acid into prostaglandins G2, H2, and the latter into thromboxane A2. In addition, calcium activates platelet contractile proteins, which enhances their aggregation and release reaction.

Thrombospondin- a glycoprotein that is produced by the vascular endothelium, but is also found in platelets. Forms complexes with collagen, heparin, and is a strong aggregating factor, mediating platelet adhesion to the subendothelium.

A number of other factors, in addition to the above, contribute to an increase in the thrombogenicity of blood vessels when they are damaged or dysfunctional. Subendothelial structures, especially collagen, have adhesive and aggregating properties.

Collagen- the most common and durable compound is associated, sticky glycoproteins and proteoglycans. Mature collagen consists of a triple polypeptide chain and is stabilized by numerous bonds. There are about 19 types of collagen, differing in fibril thickness, fibrousness or amorphousness. Collagen is formed in fibroblasts, smooth muscles, and endothelium. Vitamin C plays an important role in its formation.

Collagen is present in collagen fibers, basement membranes, amorphous ground substance of connective tissue, binds components intercellular substance with components of cell membranes. Collagens, especially types I and III, have strong aggregating properties: with the participation of adhesive proteins (fibronectin and VIII-WF), they fix platelets.

A major role in the activation of platelets is played by ATP, its energy and breakdown products (ADP), formed when the endothelium is damaged. Hydrolysis of ATP, which platelets are rich in, also occurs. Therefore, at the site of vessel damage where platelets accumulate, due to the abundance of thromboaggregating factors, including ADP, a lot of energy will be released, which is necessary for platelet activation processes.

Conclusion. Advances in recent years in the study of the structure and function of the vascular endothelium have discovered completely new properties, which has contributed to the introduction of new forms of drugs. The endothelium turned out to be a huge endocrine gland that produces wide range biologically active substances. Biologically active substances of the endothelium are involved in many mechanisms of homeostasis, including the regulation of local blood flow. The composition of biologically active substances produced by the endothelium is determined by the state of the latter. In the physiological state, endothelial BAS create conditions for adequate local blood flow, synthesizing powerful anticoagulants, which are also vasodilators. The activity of the endothelium normally ensures the trophism of organs and performs a protective function due to the presence of highly organized self-regulation mechanisms in the endothelium.

When the function or structure of the endothelium is disrupted, the spectrum of biologically active substances secreted by it changes dramatically. The endothelium begins to secrete aggregates, coagulants, vasoconstrictors, and some of them (the renin-angiotensin system) affect the entire cardiovascular system. Under unfavorable conditions (hypoxia, metabolic disorders, atherosclerosis, etc.), the endothelium becomes an initiator (or modulator) of many pathological processes in the body.

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Disorders of the functional state of the vascular endothelium in clinical conditions can be diagnosed using biochemical and functional markers. Biochemical markers of damaged endothelium include increased concentrations in the blood of biologically active substances synthesized by the endothelium or expressed on its surface.

The most significant of them:

von Willebrand factor;

Endothelium-1;

Adhesion molecules (E-selectin, P-selectin, VCAM-1, etc.);

Tissue plasminogen activator;

Thrombomodulin;

Fibronectin.

Von Willebrand factor (vWf) is a glycoprotein synthesized by vascular endothelial cells. Its concentration in blood plasma normally does not exceed 10 mcg/ml. Von Willebrand factor is necessary for the normal functioning of blood clotting factor VIII. Another important function of factor VIII is the formation of platelet aggregates at sites of damaged endothelium. In these cases, vWf binds to the subendothelium and forms a bridge between the surface of the subendothelium and platelets. The importance of vWf in the regulation of the hemostatic system is also confirmed by the fact that with congenital inferiority or dysfunction of this protein, a fairly frequently observed disease develops - von Willebrand disease. A number of prospective studies performed in recent years have shown that high levels of vWf in individuals with cardiovascular pathology may be important for predicting the likelihood of myocardial infarction and death. It is believed that the vWf level reflects the degree of damage to the vascular endothelium. Vopei et al. were the first to propose determining the level of vWf in plasma to assess the degree of damage to the vascular endothelium. The hypothesis they proposed was based on the fact that in patients with obliterating atherosclerosis of the extremities or septicemia, an increased level of vWf directly reflected the extent of vascular lesion. Subsequent studies have shown an increase in vWf levels in various clinical conditions with damage to endothelial cells and exposure of the subendothelial layer (with hypertension, acute and chronic renal failure, DN and vasculitis).

Data obtained in the nephropathy department of the State Research Center of the Russian Academy of Medical Sciences indicate that as the severity of hypertension and diabetic kidney damage increases, the concentration of vWf in the blood plasma increases, which indicates severe damage to the vascular endothelium (Fig. 5.3).

Endotepin-l. In 1988, M. Yanagisawa et al. characterized the endothelial-derived vasoconstrictor as a peptide consisting of 21 amino acid residues and named it endothelin. Further research showed that there is a family of endothelins, which consists of at least 4 endothelin peptides with a similar chemical structure. Currently studied

on chemical structure endothelin-1, endothelin-2 and endothelin-3. Most (up to 70-75%) of endothelin-1 is secreted by endothelial cells towards the smooth muscle cells of the vascular wall. The binding of endothelin-1 to specific receptors on the membranes of smooth muscle cells leads to their contraction and, ultimately, to vasoconstriction. Animal experiments have shown that in vivo endothelins are the most powerful vasoconstrictor factors currently known.

In a study conducted at the State Research Center of the Russian Academy of Medical Sciences, we showed that in patients with diabetes, the concentration of endothelin-1 increases as the severity of DN and hypertension increases (Fig. 5.4).

Adhesion molecules. Markers of activated endothelium and leukocytes are soluble forms of adhesion molecules in the blood serum (Adams, 1994). The adhesion molecules of the selectin and immunoglobulin families (E-selectin, intercellular molecules - ICAM-1, -2, -3 and surface adhesion molecule - VCAM-1) have the greatest diagnostic significance.

E-selectin, or ELAM-1 (English: Endothelial Leucocyte Adhesion Molecule) is an adhesion molecule detected on endothelial cells. When exposed to damaging factors, the activated endothelium synthesizes and expresses this molecule, which creates the prerequisites for subsequent receptor interaction, which is realized in the adhesion of leukocytes and platelets with the development of blood stasis.

ICAM-1 (English Intercellular Adhesion Molecule, CD54) is an adhesion molecule of hematopoietic and non-hematopoietic cells. Strengthens

the expression of this molecule is affected by IL-2, tumor necrosis factor a. ICAM-1 can exist in membrane-bound and soluble (serum) forms (sICAM-1). The latter appears in the blood serum as a result of proteolysis and exfoliation of ICAM-1 from the membrane of ICAM-1-positive cells. The amount of serum sICAM-1 correlates with the severity clinical manifestations disease and can serve as a sign of the activity of the process.

VCAM-1 (Vascular Cellular Adhesion Molecule, CD106) is a vascular cell adhesion molecule expressed on the surface of activated endothelium and other cell types. The appearance of a soluble biologically active form of sVCAM-I in serum can also occur as a result of proteolysis and reflect the activity of the process.

The listed adhesion molecules (E-selectin, 1CAM-1 and VCAM-1) are considered as possible main markers reflecting the process of activation of endothelial cells and leukocytes.

The increase in microvascular complications and hypertension in diabetes is accompanied by an increase in the expression of adhesion molecules, indicating severe and irreversible damage to endothelial cells.

A functional marker of damaged endothelium is a violation of endothelium-dependent vascular vasodilation, the preservation of which is ensured by the secretion of NO. It is he who plays the role of moderator of the main functions of the endothelium. This compound regulates the activity and sequence of launch of all other biologically active substances produced by the endothelium. NO not only causes vasodilation, but also blocks the proliferation of smooth muscle cells, prevents the adhesion of blood cells and has antiplatelet properties. Thus, NO is a basic factor in antiatherogenesis.

Unfortunately, the NO-producing function of the endothelium is the most vulnerable. The reason for this is the high instability of the NO molecule, by its nature free radical. As a result, the beneficial antiatherogenic effect of NO is leveled out and is inferior to the toxic atherogenic effect of other factors of damaged endothelium.

Due to the high instability of the NO molecule, direct measurement of its concentration in the blood is almost impossible. Therefore, to assess the NO-synthetic function of the endothelium, indirect and non-invasive method, based on studying the response of the endothelium to various stimuli (in particular, reactive hyperemia). In this case, the change in the diameter of the brachial or radial artery is examined (using high-resolution Doppler ultrasound) in response to its short-term clamping (5 minutes) using a pneumatic cuff. The expansion of the brachial artery after such clamping is due to the release of NO by the endothelium of the arteries. Evidence of the endothelial dependence of arterial dilation was obtained in studies using a specific NO inhibitor - L-NMMA, which reduced the observed dilatation effect by almost 70%. Normally, endothelium-dependent dilatation of the brachial artery in response to reactive hyperemia is 8-10%. A decrease in this indicator indicates low production of NO by the vascular endothelium.

A study conducted at the State Research Center of the Russian Academy of Medical Sciences convincingly demonstrated that as the severity of hypertension and DN increases, endothelium-dependent vasodilation of the brachial artery decreases, which indicates a pronounced dysfunction of the endothelium in these patients.