Home Thyroid gland Endothelial damage. Endothelial dysfunction: manifestations, examinations, treatment. Pharmacological methods for correcting endothelial dysfunction in patients with CCI

Endothelial damage. Endothelial dysfunction: manifestations, examinations, treatment. Pharmacological methods for correcting endothelial dysfunction in patients with CCI

Chronic cerebral ischemia (CHI) is a disease with progressive multifocal diffuse brain damage, manifested by neurological disorders of varying degrees, caused by a reduction in cerebral blood flow, transient ischemic attacks or previous cerebral infarctions. The number of patients with symptoms of chronic cerebral ischemia in our country is steadily growing, amounting to at least 700 per 100,000 population.

Depending on the severity of clinical disorders, three stages of the disease are distinguished. Each stage in turn can be compensated, subcompensated and decompensated. In stage I, headaches, a feeling of heaviness in the head, dizziness, sleep disturbances, decreased memory and attention are observed, in the neurological status - scattered small-focal neurological symptoms, insufficient for diagnosing the delineated neurological syndrome. In stage II, the complaints are similar, but more intense - memory progressively deteriorates, unsteadiness when walking occurs, difficulties arise in professional activities; clear symptoms of organic, neurological lesions of the brain appear. Stage III is characterized by a decrease in the number of complaints, which is associated with the progression of cognitive impairment and a decrease in criticism of one’s condition. In the neurological status, a combination of several neurological syndromes is observed, which indicates multifocal brain damage.

The role of endothelial dysfunction in the pathogenesis of atherosclerosis and arterial hypertension

The main factors leading to the development of chronic cerebral ischemia are atherosclerotic vascular damage and arterial hypertension (AH).

Risk factors for the development of cardiovascular diseases, such as hypercholesterolemia, arterial hypertension, diabetes mellitus, smoking, hyperhomocysteinemia, obesity, physical inactivity, are accompanied by impaired endothelium-dependent vasodilation.

Endothelium is a single-layer layer of flat cells of mesenchymal origin, lining the inner surface of blood and lymphatic vessels and cardiac cavities. To date, numerous experimental data have been accumulated that allow us to speak about the role of the endothelium in maintaining homeostasis by maintaining the dynamic balance of a number of multidirectional processes:

vascular tone (regulation of vasodilation/vasoconstriction processes through the release of vasodilator and vasoconstrictor factors, modulation of the contractile activity of smooth muscle cells);
hemostasis processes (synthesis and inhibition of platelet aggregation factors, pro- and anticoagulants, fibrinolysis factors);
local inflammation (production of pro- and anti-inflammatory factors, regulation of vascular permeability, leukocyte adhesion processes);
anatomical structure and vascular remodeling (synthesis/inhibition of proliferation factors, growth of smooth muscle cells, angiogenesis).

The endothelium also performs transport (carries out two-way transport of substances between the blood and other tissues) and receptor functions (endotheliocytes have receptors for various cytokines and adhesive proteins, express on the plasmalemma a number of compounds that ensure adhesion and transendothelial migration of leukocytes).

An increase in blood flow velocity leads to increased formation of vasodilators in the endothelium and is accompanied by an increase in the formation of endothelial NO synthase and other enzymes in the endothelium. Shear stress is of great importance in the autoregulation of blood flow. Thus, with an increase in arterial vascular tone, the linear velocity of blood flow increases, which is accompanied by an increase in the synthesis of endothelial vasodilators and a decrease in vascular tone.

Endothelium-dependent vasodilation (EDVD) is associated with the synthesis in the endothelium of mainly three main substances: nitrogen monoxide (NO), endothelial hyperpolarizing factor (EDHF) and prostacyclin. Basal NO secretion determines the maintenance of normal vascular tone at rest. A number of factors, such as acetylcholine, adenosine triphosphoric acid (ATP), bradykinin, as well as hypoxia, mechanical deformation and shear stress, cause the so-called stimulated secretion of NO, mediated by the second messenger system.

Normally, NO is a powerful vasodilator and also inhibits the processes of remodeling of the vascular wall, suppressing the proliferation of smooth muscle cells. It prevents platelet adhesion and aggregation, monocyte adhesion, protects the vascular wall from pathological changes and the subsequent development of atherosclerosis and atherothrombosis.

With prolonged exposure to damaging factors, a gradual disruption of the functioning of the endothelium occurs. The ability of endothelial cells to release relaxing factors decreases, while the formation of vasoconstrictor factors persists or increases, i.e., a condition defined as “endothelial dysfunction” is formed. Pathological changes occur in vascular tone (general vascular resistance and blood pressure), vascular structure (structural preservation of the layers of the vascular wall, manifestations of atherogenesis), immunological reactions, inflammation processes, thrombus formation, fibrinolysis.

A number of authors provide a more “narrow” definition of endothelial dysfunction - a state of the endothelium in which there is insufficient production of NO, since NO is involved in the regulation of almost all endothelial functions and, in addition, is the factor most sensitive to damage.

There are 4 mechanisms through which endothelial dysfunction is mediated:

1) impaired bioavailability of NO due to:

reduction of NO synthesis when NO synthase is inactivated;
a decrease in the density of muscarinic and bradykinin receptors on the surface of endothelial cells, irritation of which normally leads to the formation of NO;
increased NO degradation—NO destruction occurs before the substance reaches its site of action (during oxidative stress);

2) increased activity of angiotensin-converting enzyme (ACE) on the surface of endothelial cells;

3) increased production of endothelin-1 and other vasoconstrictor substances by endothelial cells;

4) violation of the integrity of the endothelium (de-endothelialization of the intima), as a result of which circulating substances, directly interacting with smooth muscle cells, cause their contraction.

Endothelial dysfunction (ED) is a universal mechanism in the pathogenesis of arterial hypertension (AH), atherosclerosis, cerebrovascular diseases, diabetes mellitus, and coronary heart disease. Moreover, endothelial dysfunction both itself contributes to the formation and progression of the pathological process, and the underlying disease often aggravates endothelial damage.

With hypercholesterolemia, cholesterol and low-density lipoproteins (LDL) accumulate on the walls of blood vessels. Low density lipoproteins are oxidized; the consequence of this reaction is the release of oxygen radicals, which, in turn, interacting with already oxidized LDL, can further enhance the release of oxygen radicals. Such biochemical reactions create a kind of pathological vicious circle. Thus, the endothelium is constantly exposed to oxidative stress, which leads to increased decomposition of NO by oxygen radicals and weakened vasodilation. As a result, DE is realized in changes in the structure of the vascular wall or vascular remodeling in the form of thickening of the vessel media, a decrease in the lumen of the vessel and the extracellular matrix. In large vessels, the elasticity of the wall decreases, the thickness of which increases, leukocyte infiltration occurs, which, in turn, predisposes to the development and progression of atherosclerosis. Remodeling of blood vessels leads to disruption of their function and typical complications of hypertension and atherosclerosis - myocardial infarction, ischemic stroke, renal failure.

With the predominant development of atherosclerosis, NO deficiency accelerates the development of atherosclerotic plaque from a lipid spot to a crack in the atherosclerotic plaque and the development of atherothrombosis. Hyperplasia and hypertrophy of smooth muscle cells increases the degree of vasoconstrictor response to neurohumoral regulation, increases peripheral vascular resistance and is thus a factor stabilizing hypertension. An increase in systemic blood pressure is accompanied by an increase in intracapillary pressure. Increased intramural pressure stimulates the formation of free radicals, especially superoxide anion, which, by binding to nitric oxide produced by the endothelium, reduces its bioavailability and leads to the formation of peroxynitrite, which has a cytotoxic effect on the endothelial cell and activates the mitogenesis of smooth muscle cells, there is an increased formation of vasoconstrictors, especially endothelin-1, thromboxane A2 and prostaglandin H2, which stimulates the growth of smooth muscle cells.

Diagnosis of the functional state of the endothelium

There are a large number of different methods for assessing the functional state of the endothelium. They can be divided into 3 main groups:

1) assessment of biochemical markers;
2) invasive instrumental methods for assessing endothelial function;
3) non-invasive instrumental methods for assessing endothelial function.

Biochemical assessment methods

Reduced NO synthesis or bioavailability is central to the development of DE. However, the short lifetime of the molecule severely limits the use of measuring NO in serum or urine. The most selective markers of endothelial dysfunction include: von Willebrand factor (vWF), antithrombin III, desquamated endothelial cells, the content of cellular and vascular adhesion molecules (E-selectin, ICAM-1, VCAM-1), thrombomodulin, protein C receptors, annexin -II, prostacyclin, tissue plasminogen activator t-PA, P-selectin, tissue coagulation pathway inhibitor (TFPI), protein S.

Invasive assessment methods

Invasive methods involve chemical stimulation of muscarinic endothelial receptors with endothelium-stimulating drugs (acetylcholine, methacholine, substance P) and some direct vasodilators (nitroglycerin, sodium nitroprusside), which are injected into the artery and cause endothelium-independent vasodilation (ENVD). One of the first such methods was radiocontrast angiography using intracoronary injection of acetylcholine.

Non-invasive diagnostic methods

Recently, there has been great interest in the use of photoplethysmography (PPG), i.e. recording a pulse wave using an optical sensor to assess the vasomotor effect that appears during the occlusion test of nitric oxide and the functional state of the endothelium. The most convenient place to place the PPG sensor is a finger. The formation of the PPG signal primarily involves the pulse dynamics of changes in the pulse volume of blood flow and, accordingly, the diameter of the digital arteries, which is accompanied by an increase in the optical density of the measured area. The increase in optical density is determined by pulse local changes in the amount of hemoglobin. The test results are comparable to those obtained from coronary angiography with the administration of acetylcholine. The described phenomenon underlies the functioning of the non-invasive diagnostic hardware and software complex “AngioScan-01”. The device allows you to identify the earliest signs of endothelial dysfunction. Registration technology and volumetric pulse wave contour analysis make it possible to obtain clinically significant information about the state of the stiffness of elastic arteries (the aorta and its main arteries) and the tone of small resistive arteries, as well as to assess the functional state of the endothelium of large muscular and small resistive vessels (the methodology is similar to ultrasound "cuff test")

Pharmacological methods for correcting endothelial dysfunction in patients with CCI

Methods for correcting DE in CCI can be divided into two groups:

1) elimination of factors aggressive to the endothelium (hyperlipidemia, hyperglycemia, insulin resistance, postmenopausal hormonal changes in women, high blood pressure, smoking, sedentary lifestyle, obesity) and, thus, modification and reduction of oxidative stress;
2) normalization of endothelial NO synthesis.

To solve these problems, various drugs are used in clinical practice.

Statins

Reducing the level of cholesterol in the blood plasma slows down the development of atherosclerosis and in some cases causes regression of atherosclerotic changes in the vessel wall. In addition, statins reduce lipoprotein oxidation and free radical damage to endothelial cells.

NO donors and NO synthase substrates

Nitrates (organic nitrates, inorganic nitro compounds, sodium nitroprusside) are a donor of NO, i.e., they exhibit their pharmacological effect by releasing NO from them. Their use is based on vasodilating properties that promote hemodynamic unloading of the heart muscle and stimulation of endothelium-independent vasodilation of the coronary arteries. Long-term administration of NO donors can lead to inhibition of its endogenous synthesis in the endothelium. It is with this mechanism that the possibility of accelerated atherogenesis and the development of hypertension is associated with their chronic use.

L-arginine is a substrate of endothelial NO synthase, leading to improved endothelial function. However, the experience of its use in patients with hypertension and hypercholesterolemia has only theoretical significance.

Dihydropyridine calcium antagonists improve EDVD by increasing NO (nifedipine, amlodipine, lacidipine, pranidipine, felodipine, etc.).

ACE inhibitors and AT-II antagonists

In experiments, EDVD could be improved with the help of angiotensin-converting enzyme inhibitors and angiotensin-2 antagonists. ACE inhibitors increase the bioavailability of NO by reducing the synthesis of angiotensin-2 and increasing plasma bradykinin levels.

Other antihypertensive drugs

Beta blockers have vasodilating properties due to stimulation of NO synthesis in the vascular endothelium and activation of the L-arginine/NO system, as well as the ability to stimulate NO synthase activity in endothelial cells.

Thiazide diuretics lead to increased NO synthase activity in endothelial cells. Indapamide has a direct vasodilating effect through putative antioxidant properties, increasing the bioavailability of NO and reducing its breakdown.

Antioxidants

Given the role of oxidative stress in the pathogenesis of endothelial dysfunction, it is expected that the administration of antioxidant therapy may become a leading strategy in its treatment. The reverse development of endothelial dysfunction in the coronary and peripheral arteries has been proven with the use of glutathione, N-acetyl cysteine, and vitamin C. Drugs with antioxidant and antihypoxic activity can improve endothelial function.

Thioctic acid (TA, alpha lipoic acid)

The protective role of MC in relation to endothelial cells from extra- and intracellular oxidative stress has been demonstrated in cell culture. In the ISLAND study in patients with metabolic syndrome, TC contributed to an increase in EDVD of the brachial artery, which was accompanied by a decrease in the plasma levels of interleukin-6 and plasminogen activator-1. TC affects energy metabolism, normalizes NO synthesis, reduces oxidative stress and increases the activity of the antioxidant system, which may also explain the decrease in the degree of brain damage during ischemia-reperfusion.

Vinpocetine

Numerous studies have shown an increase in volumetric cerebral blood flow with the use of this drug. It is assumed that vinpocetine is not a classic vasodilator, but relieves existing vasospasm. It enhances the utilization of oxygen by nerve cells, inhibits the entry and intracellular release of calcium ions.

Deproteinized hemoderivative of calf blood (Actovegin)

Actovegin is a highly purified hemoderivative of calf blood, consisting of more than 200 biologically active components, including amino acids, oligopeptides, biogenic amines and polyamines, sphingolipids, inositol phosphooligosaccharides, metabolic products of fats and carbohydrates, free fatty acids. Actovegin increases the consumption and use of oxygen, thereby activating energy metabolism, shifting cell energy metabolism towards aerobic glycolysis, inhibiting the oxidation of free fatty acids. At the same time, the drug also increases the content of high-energy phosphates (ATP and ADP) under conditions of ischemia, thereby replenishing the resulting energy deficit. In addition, Actovegin also prevents the formation of free radicals and blocks apoptosis processes, thereby protecting cells, especially neurons, from death under conditions of hypoxia and ischemia. There is also a significant improvement in cerebral and peripheral microcirculation against the background of improved aerobic energy exchange of vascular walls and the release of prostacyclin and nitric oxide. The resulting vasodilation and decrease in peripheral resistance are secondary to the activation of oxygen metabolism of the vascular walls.

The results obtained by A. A. Fedorovich convincingly prove that Actovegin not only has a pronounced metabolic effect, increasing the functional activity of the microvascular endothelium, but also affects the vasomotor function of microvessels. The vasomotor effect of the drug is most likely realized through an increase in the production of NO by the microvascular endothelium, which results in a significant improvement in the functional state of the microvascular smooth muscle apparatus. However, a direct myotropic positive effect cannot be excluded.

In recent work, a group of authors studied the role of Actovegin as an endothelial protector in patients with CCI. With its use, patients recorded an improvement in blood flow in the carotid and vertebrobasilar systems, which correlated with an improvement in neurological symptoms and was confirmed by indicators of normalization of the functional state of the endothelium.

Despite the emergence of individual scientific studies, the problem of early diagnosis of endothelial dysfunction in CCI remains insufficiently studied. At the same time, timely diagnosis and subsequent pharmacological correction of DE will significantly reduce the number of patients with cerebrovascular diseases or achieve maximum regression of the clinical picture in patients with different stages of chronic cerebral ischemia.

Literature

A. I. Fedin,
E. P. Starykh 1
M. V. Putilina, Doctor of Medical Sciences, Professor
E. V. Starykh,Doctor of Medical Sciences, Professor
O. P. Mironova, Candidate of Medical Sciences
K. R. Badalyan

In the early 1980s, Furchgott and Zawadzki found that acetylcholine imparts vasodilation only when the endothelium is intact. Since that time, the level of knowledge about the function and pathophysiology of the endothelium has increased exponentially.

Today we know that the endothelium performs a key function in the regulation of vascular tone, vascular growth, in the processes of leukocyte adhesion and in the balance of profibrinolytic and prothrombogenic activity. The decisive role here is played by nitric oxide (NO) produced in the endothelium. Nitric oxide performs an important function in the regulation of coronary blood flow, namely, it expands or narrows the lumen of blood vessels according to need. An increase in blood flow, for example, during physical activity, due to the shearing forces of flowing blood, leads to mechanical irritation of the endothelium. This mechanical irritation stimulates the synthesis of NO, which, leaving the lumen, causes relaxation of the vascular muscles and thus acts as a vasodilator. Other factors, for example, acetylcholine, which also affects the synthesis of NO through specific receptors, simultaneously have the ability to cause vasoconstriction directly through contractions of smooth muscle cells (Fig. 1). If endothelial function is normal, then the vasodilating effect of acetylcholine outweighs. When the endothelium is damaged, the balance is disturbed towards vasoconstriction. This imbalance between vasodilation and vasoconstriction characterizes a condition called endothelial dysfunction. In practice, this means: intracoronary administration of acetylcholine with a healthy endothelium and its normal function causes dilatation of the coronary arteries. And with the development of arteriosclerosis or in the presence of coronary risk factors, paradoxical vasoconstriction is observed.

Causes of endothelial dysfunction

The unprotected position of the endothelium, which, as a single-celled inner layer, covers the walls of blood vessels from the inside, makes it vulnerable to various influences and known cardiovascular risk factors. For example, with hypercholesterolemia, low-density lipoprotein cholesterol accumulates on the walls of blood vessels. Low-density lipoprotein cholesterol is oxidized, releasing oxygen radicals, which again attracts monocytes. They can penetrate the vascular wall and interact with oxidized low-density lipoproteins and enhance the release of oxygen radicals. Thus, the endothelium is exposed to oxidative stress. Oxidative stress refers to the increased decomposition of NO by oxygen radicals, which leads to weakened vasodilation. Accordingly, patients with hypercholesterolemia exhibit paradoxical vasoconstriction after stimulation with acetylcholine.

Arterial hypertension also changes the morphology and function of the endothelium. Compared to patients with normal blood pressure, these cases develop an enhanced interaction of platelets and monocytes with endothelial cells, and increased blood pressure also favors oxidative stress on the vessel wall, resulting in a decrease in endothelium-dependent vasodilation. With age, endothelial NO synthesis decreases and, equally, increased endothelial reactivity to vasoconstrictor factors develops. Smoking is a significantly harmful factor for endothelial function. After nicotine consumption, circulating endothelial cells in the peripheral blood double, and this is a sign of an enhanced cell cycle and desquamation (“squamation”) of the endothelium. Already at a young age, smokers exhibit increased endothelial vulnerability and a tendency toward increased endothelial dysfunction in accordance with age and the amount of nicotine consumed.

People suffering from diabetes mellitus often exhibit an extremely accelerated form of arteriosclerotic changes. Endothelial dysfunction caused by chronically elevated blood sugar levels is discussed as its cause. Experimental studies have shown that elevated glucose concentrations lead to paradoxical vasoconstriction in response to acetylcholine administration. Obviously, the causative role here is played not so much by a violation of NO metabolism, but by the increased formation of vasoconstrictor prostaglandins, which counteract the vasodilation transmitted by NO. Along with the classical risk factors for atherosclerotic changes in blood vessels, the development of endothelial dysfunction with reduced activity of NO synthesis may also be influenced by a lack of physical mobility.

Therapeutic Strategies for Endothelial Dysfunction

The goal of therapy for endothelial dysfunction is to eliminate paradoxical vasoconstriction and, through increased NO availability in the vessel wall, to create a protective environment against atherosclerotic changes. The main goals for effective therapy are the elimination of cardiovascular risk factors and improvement of the availability of endogenous NO through stimulation of NO synthetase or inhibition of NO breakdown (Table 1).

Non-drug methods for treating endothelial dysfunction include: diet therapy aimed at reducing serum cholesterol levels, systematic physical activity and cessation of cigarette and alcohol consumption. It is believed that the use of antioxidants, for example, vitamins E and C, can improve the situation with endothelial dysfunction. Thus, Levine GE et al. (1996) showed that after oral administration of 2 g of vitamin C in patients with coronary artery disease there was a significant short-term improvement in endothelium-dependent vasodilation of Arteria brachialis during reactive hyperemia. Moreover, the authors discussed the capture of oxygen radicals by vitamin C and thus better availability of NO as a mechanism of action. According to some authors, there is also evidence for the use of calcium channel blockers and estrogen replacement therapy in relation to the positive effect on endothelial dysfunction. However, it has not yet been possible to explain the mechanism of action in detail. For therapeutic effects on coronary tone, nitrates have long been used, which are capable of releasing NO to the walls of blood vessels, regardless of the functional state of the endothelium (Fig. 1). But although nitrates, due to the dilation of stenotic vascular segments and their hemodynamic effects, are certainly effective in reducing myocardial ischemia, they do not lead to long-term improvement in endothelium-mediated vascular regulation of the coronary vascular bed. As Harrison DG and Bates JN (1999) established, the demand-oriented rhythmicity of changes in vascular tone, which is controlled by endogenous NO, cannot be stimulated by exogenously administered NO. If we look from the point of view of influencing the cause of endothelial dysfunction, then improvement could be achieved by reducing elevated cholesterol levels and the corresponding oxidative stress in the vascular wall. And in fact, it has already been shown that after 6 months of therapy with human gonadotropin hormone coenzyme A reductase inhibitors, it was possible to achieve an improvement in the vasomotor response of the coronary arteries (Anderson TJ et al. (1995), Egashira K. et al. (1994)). Gould KL et al. (1994) showed that a very dramatic reduction in cholesterol after just 6 weeks led to a functional improvement in myocardial perfusion under stress.

The role of the reninangiotensin system (RAS) in relation to endothelial dysfunction is mainly based on the vasoconstrictor effectiveness of angiotensin II. One of the first studies to show improvement in endothelial dysfunction with the ACE inhibitor quinapril was the TREND trial (completed in 1996). After 6 months of quinapril therapy, this study observed a significant improvement in paradoxical acetylcholine-induced epicardial coronary vasoconstriction compared with patients in the placebo group. It is tempting to count this result on account of the reduced formation of angiotensin II. As an additional benefit, reduced degradation of the vasodilatory bradykinin via angiotensin-converting enzyme inhibition may play a significant role in improving endothelial-mediated vasodilation during ACE inhibitor therapy. Another study has now been completed (Quo Vadis (1998)), which showed that patients with coronary artery disease after coronary artery bypass grafting who were treated with the ACE inhibitor quinapril developed ischemic complications much less frequently than patients who did not receive such treatment. To what extent is the improvement in endothelial dysfunction with human gonadotropin hormone coenzyme A reductase inhibitors and ACE inhibitors an epiphenomenon or do the beneficial effects of these two classes of substances play a causal role in increasing life expectancy in patients with coronary heart disease (4S, SOLVD, SAVE studies) , CONSENSUS II). Currently, these questions remain open.

The practical significance of endothelial dysfunction lies in understanding the imbalance between vasoprotective factors and factors of vascular damage. Diagnosis of endothelial damage based on paradoxical vasoconstriction, for example, with the administration of acetylcholine, can be carried out even before the appearance of macroscopically visible vessel damage. Thanks to this, it is possible, especially in patients at risk, for example, with familial hypercholesterolemia or arterial hypertension, by minimizing risk factors and specific pharmacological effects (human ganadotropin hormone coenzyme A reductase inhibitors, ACE inhibitors, antioxidants, cholesterol synthesis inhibitors, etc. .) overcome endothelial dysfunction or at least reduce it and may even improve the prognosis in such patients.

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 damage. 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 the chemical structure of 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 (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 of clinical manifestations of the 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, which is a free radical by nature. 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 practically impossible. Therefore, to assess the NO-synthetic function of the endothelium, an indirect and non-invasive method is used, 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 impairment of endothelial function in these patients.

Catad_tema Arterial hypertension - articles

Endothelial dysfunction as a new concept for the prevention and treatment of cardiovascular diseases

The end of the 20th century was marked not only by the intensive development of fundamental concepts of the pathogenesis of arterial hypertension (AH), but also by a critical revision of many ideas about the causes, mechanisms of development and treatment of this disease.

Currently, hypertension is considered as a complex complex of neurohumoral, hemodynamic and metabolic factors, the relationship of which is transformed over time, which determines not only the possibility of transition from one variant of the course of hypertension to another in the same patient, but also the deliberate simplification of ideas about a monotherapeutic approach , and even the use of at least two drugs with a specific mechanism of action.

Page’s so-called “mosaic” theory, being a reflection of the established traditional conceptual approach to the study of hypertension, which based hypertension on particular violations of the mechanisms of blood pressure regulation, may be partly an argument against the use of one antihypertensive drug for the treatment of hypertension. At the same time, such an important fact is rarely taken into account that in its stable phase, hypertension occurs with normal or even reduced activity of most systems that regulate blood pressure.

Currently, serious attention in views on hypertension has begun to be paid to metabolic factors, the number of which, however, is increasing with the accumulation of knowledge and laboratory diagnostic capabilities (glucose, lipoproteins, C-reactive protein, tissue plasminogen activator, insulin, homocysteine and others).

The possibilities of 24-hour BP monitoring, the peak of which was introduced into clinical practice in the 80s, showed a significant pathological contribution of impaired 24-hour BP variability and features of circadian BP rhythms, in particular, a pronounced pre-dawn rise, high diurnal BP gradients and the absence of a nocturnal decrease in BP, which largely associated with fluctuations in vascular tone.

However, by the beginning of the new century, a direction had clearly crystallized, which largely included the accumulated experience of fundamental developments on the one hand, and focused the attention of clinicians on a new object - the endothelium - as the target organ of hypertension, the first to come into contact with biologically active substances and most early damaged in hypertension.

On the other hand, the endothelium implements many links in the pathogenesis of hypertension, directly participating in the increase in blood pressure.

The role of the endothelium in cardiovascular pathology

In the form familiar to 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.

The barrier role of the vascular endothelium as an active organ determines its main role in the human body: maintaining homeostasis by regulating the equilibrium state of opposing processes - a) vascular tone (vasodilation/vasoconstriction); b) anatomical structure of blood vessels (synthesis/inhibition of proliferation factors); c) hemostasis (synthesis and inhibition of fibrinolysis and platelet aggregation factors); d) local inflammation (production of pro- and anti-inflammatory factors).

It should be noted that each of the four functions of the endothelium, which determines the thrombogenicity of the vascular wall, inflammatory changes, vasoreactivity and stability of the atherosclerotic plaque, is directly or indirectly related to the development and progression of atherosclerosis, hypertension and its complications. Indeed, recent studies have shown that plaque tears leading to myocardial infarction do not always occur in the area of maximum stenosis of the coronary artery; on the contrary, they often occur in areas of small narrowing - less than 50% according to angiography.

Thus, the study of the role of the endothelium in the pathogenesis of cardiovascular diseases (CVD) has led to the understanding that the endothelium regulates not only peripheral blood flow, but also other important functions. That is why the concept of the endothelium as a target for the prevention and treatment of pathological processes leading to or realizing CVD has become a unifying concept.

Understanding the multifaceted role of the endothelium at a qualitatively new level again leads to the fairly well-known but well-forgotten formula “a person’s health is determined by the health of his blood vessels.”

In fact, by the end of the 20th century, namely in 1998, after receiving the Nobel Prize in the field of medicine by F. Murad, Robert Furshgot and Luis Ignarro, a theoretical basis was formed for a new direction of fundamental and clinical research in the field of hypertension and other CVDs - the development the participation of the endothelium in the pathogenesis of hypertension and other CVDs, as well as ways to effectively correct its dysfunction.

It is believed that drug or non-drug interventions in the early stages (pre-disease or early stages of the disease) can delay its onset or prevent progression and complications. The leading concept of preventive cardiology is based on the assessment and correction of so-called cardiovascular risk factors. The unifying principle for all such factors is that sooner or later, directly or indirectly, they all cause damage to the vascular wall, and above all, in its endothelial layer.

Therefore, it can be assumed that at the same time they are also risk factors for endothelial dysfunction (ED) as the earliest phase of damage to the vascular wall, atherosclerosis and hypertension, in particular.

DE is, first of all, an imbalance between the production of vasodilating, angioprotective, antiproliferative factors on the one hand (NO, prostacyclin, tissue plasminogen activator, C-type natriuretic peptide, endothelial hyperpolarizing factor) and vasoconstrictive, prothrombotic, proliferative factors, on the other hand ( endothelin, superoxide anion, thromboxane A2, tissue plasminogen activator inhibitor). At the same time, the mechanism for their final implementation is unclear.

One thing is obvious - sooner or later, cardiovascular risk factors upset the delicate balance between the most important functions of the endothelium, which ultimately results in the progression of atherosclerosis and cardiovascular incidents. Therefore, the basis of one of the new clinical directions was the thesis about the need to correct endothelial dysfunction (i.e., normalize endothelial function) as an indicator of the adequacy of antihypertensive therapy. The evolution of the goals of antihypertensive therapy has been specified not only to the need to normalize blood pressure levels, but also to normalize endothelial function. In fact, this means that reducing blood pressure without correcting endothelial dysfunction (ED) cannot be considered a successfully solved clinical problem.

This conclusion is fundamental, also because the main risk factors for atherosclerosis, such as hypercholesterolemia, hypertension, diabetes mellitus, smoking, hyperhomocysteinemia, are accompanied by impaired endothelium-dependent vasodilation - both in the coronary and peripheral bloodstream. And although the contribution of each of these factors to the development of atherosclerosis has not been fully determined, this does not yet change the prevailing ideas.

Among the abundance of biologically active substances produced by the endothelium, the most important is nitric oxide - NO. The discovery of the key role of NO in cardiovascular homeostasis was awarded the Nobel Prize in 1998. Today it is the most studied molecule involved in the pathogenesis of hypertension and CVD in general. Suffice it to say that the disrupted relationship between angiotensin II and NO is quite capable of determining the development of hypertension.

Normally functioning endothelium is characterized by continuous basal production of NO via endothelial NO synthetase (eNOS) from L-arginine. This is necessary to maintain normal basal vascular tone. At the same time, NO has angioprotective properties, suppressing the proliferation of vascular smooth muscle and monocytes, thereby preventing pathological restructuring of the vascular wall (remodeling) and the progression of atherosclerosis.

NO has an antioxidant effect, inhibits platelet aggregation and adhesion, endothelial-leukocyte interactions and monocyte migration. Thus, NO is a universal key angioprotective factor.

In chronic CVD, as a rule, there is a decrease in NO synthesis. There are many reasons for this. To sum it all up, it is obvious that a decrease in NO synthesis is usually associated with impaired expression or transcription of eNOS, including metabolic origin, a decrease in the availability of L-arginine reserves for endothelial NOS, accelerated NO metabolism (with increased formation of free radicals) or a combination thereof.

With all the versatility of the effects of NO, Dzau et Gibbons were able to schematically formulate the main clinical consequences of chronic NO deficiency in the vascular endothelium, thereby showing, using a model of coronary heart disease, the real consequences of DE and drawing attention to the exceptional importance of its correction at the earliest possible stages.

An important conclusion follows from Scheme 1: NO plays a key angioprotective role even in the early stages of atherosclerosis.

Scheme 1. MECHANISMS OF ENDOTHELIAL DYSFUNCTION
FOR CARDIOVASCULAR DISEASES

Thus, it has been proven that NO reduces the adhesion of leukocytes to the endothelium, inhibits transendothelial migration of monocytes, maintains normal endothelial permeability for lipoproteins and monocytes, and inhibits the oxidation of LDL in the subendothelium. NO is able to inhibit the proliferation and migration of vascular smooth muscle cells, as well as their synthesis of collagen. The administration of NOS inhibitors after vascular balloon angioplasty or in conditions of hypercholesterolemia led to intimal hyperplasia, and, conversely, the use of L-arginine or NO donors reduced the severity of induced hyperplasia.

NO has antithrombotic properties, inhibiting platelet adhesion, their activation and aggregation, activating tissue plasminogen activator. There is emerging evidence that NO is an important factor modulating the thrombotic response to plaque rupture.

And of course, NO is a powerful vasodilator that modulates vascular tone, leading to vasorelaxation indirectly through an increase in cGMP levels, maintaining basal vascular tone and carrying out vasodilation in response to various stimuli - blood shear stress, acetylcholine, serotonin.

Impaired NO-dependent vasodilation and paradoxical vasoconstriction of epicardial vessels acquires particular clinical significance for the development of myocardial ischemia under conditions of mental and physical stress, or cold stress. And given that myocardial perfusion is regulated by resistive coronary arteries, the tone of which depends on the vasodilatory ability of the coronary endothelium, even in the absence of atherosclerotic plaques, NO deficiency in the coronary endothelium can lead to myocardial ischemia.

Endothelial function assessment

A decrease in NO synthesis is the main factor in the development of DE. Therefore, it would seem that nothing could be simpler than measuring NO as a marker of endothelial function. However, the instability and short lifetime of the molecule sharply limit the application of this approach. The study of stable metabolites of NO in plasma or urine (nitrates and nitrites) cannot be routinely used in the clinic due to the extremely high requirements for preparing the patient for the study.

In addition, studying nitric oxide metabolites alone is unlikely to provide valuable information about the state of nitrate-producing systems. Therefore, if it is impossible to simultaneously study the activity of NO synthetases, along with a carefully controlled process of patient preparation, the most realistic way to assess the state of the endothelium in vivo is to study endothelium-dependent vasodilation of the brachial artery using an infusion of acetylcholine or serotonin, or using venous-occlusive plethysmography, and also using the latest techniques - tests with reactive hyperemia and the use of high-resolution ultrasound.

In addition to these methods, several substances are considered as potential markers of DE, the production of which may reflect endothelial function: tissue plasminogen activator and its inhibitor, thrombomodulin, von Willebrandt factor.

Therapeutic Strategies

Assessing DE as a disorder of endothelium-dependent vasodilation due to decreased NO synthesis, in turn, requires a revision of therapeutic strategies targeting the endothelium in order to prevent or reduce damage to the vascular wall.

It has already been shown that improvement in endothelial function precedes regression of structural atherosclerotic changes. Impact on bad habits - quitting smoking - leads to improved endothelial function. Fatty foods contribute to the deterioration of endothelial function in apparently healthy individuals. Taking antioxidants (vitamin E, C) helps correct endothelial function and inhibits thickening of the carotid artery intima. Physical activity improves the condition of the endothelium even in heart failure.

Improving glycemic control in patients with diabetes mellitus in itself is already a factor in the correction of DE, and normalization of the lipid profile in patients with hypercholesterolemia led to normalization of endothelial function, which significantly reduced the incidence of acute cardiovascular incidents.

At the same time, such a “specific” effect aimed at improving NO synthesis in patients with coronary artery disease or hypercholesterolemia, such as replacement therapy with L-arginine, a substrate of NOS synthetase, also leads to the correction of DE. Similar data were obtained when using the most important cofactor of NO synthetase - tetrahydrobiopterin - in patients with hypercholesterolemia.

In order to reduce NO degradation, the use of vitamin C as an antioxidant also improved endothelial function in patients with hypercholesterolemia, diabetes mellitus, smoking, arterial hypertension, and coronary artery disease. These data indicate a real possibility of influencing the NO synthesis system, regardless of the reasons that caused its deficiency.

Currently, almost all groups of drugs are being tested for their activity in relation to the NO synthesis system. An indirect effect on DE in IHD has already been shown for ACE inhibitors, which improve endothelial function indirectly through an indirect increase in the synthesis and reduction of NO degradation.

Positive results on the endothelium were also obtained in clinical trials of calcium antagonists, however, the mechanism of this effect is unclear.

A new direction in the development of pharmaceuticals, apparently, should be considered the creation of a special class of effective drugs that directly regulate the synthesis of endothelial NO and thereby directly improve endothelial function.

In conclusion, I would like to emphasize again that disturbances in vascular tone and cardiovascular remodeling lead to target organ damage and complications of hypertension. It becomes obvious that biologically active substances that regulate vascular tone simultaneously modulate a number of important cellular processes, such as proliferation and growth of vascular smooth muscle, growth of mesanginal structures, and the state of the extracellular matrix, thereby determining the rate of progression of hypertension and its complications. Endothelial dysfunction, as the earliest phase of vascular damage, is associated primarily with a deficiency in the synthesis of NO - the most important factor-regulator of vascular tone, but an even more important factor on which structural changes in the vascular wall depend.

Therefore, correction of DE in hypertension and atherosclerosis should be a routine and mandatory part of therapeutic and preventive programs, as well as a strict criterion for assessing their effectiveness.

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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 the 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 a single-layer squamous epithelium and in a calm state appears as a layer consisting of individual cells. In their shape, endothelial cells look like very thin plates of irregular shape and varying lengths. Along with elongated, spindle-shaped cells, you can often see cells with rounded ends. In the central part of the endothelial cell there is an oval-shaped nucleus. Typically, most cells have one nucleus. In addition, there are cells that do not have a nucleus. It disintegrates in the 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. In recent 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 excited endothelium, we can come to the conclusion that in different vessels endothelial cells are at different stages of differentiation. Thus, the endothelium of the sinus capillaries of the hematopoietic organs is directly connected with the surrounding reticular tissue 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 his functional state, which is largely determined by the incoming information he perceives. 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 presence of 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 an increase in blood viscosity, causing an increase in 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 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. 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 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.

Currently, endothelial dysfunction is understood as- an 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, 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. 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, 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.