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

October 30, 2017 No comments

The concept of "endothelial dysfunction" was proposed in 1960 by Williams-Kretschmer et al. to designate morphological changes in the endothelium in various pathological processes. In the future, as various aspects of this phenomenon were studied, it gradually acquired an expanded interpretation.

The concept of "endothelial dysfunction" reflects a generalized change in the functions of the endothelial lining, manifested by a disorder in the regulation of regional and / or systemic circulation, an increase in procoagulant, proaggregant antifibrinolytic activity of the blood, an increase in the pro-inflammatory potential of the body, etc.

Unlike the intact endothelium, which mainly has antiaggregant and anticoagulant potential, vasodilating and antimitogenic properties, the activity of the damaged endothelial lining promotes hemocoagulation, thrombosis, angiospasm, and proliferation of vascular wall elements. Each of these manifestations of endothelial dysfunction may have, depending on the specific conditions of their development, both pathogenic and protective-adaptive significance.

In addition to pathogenetically significant hemodynamic changes, endothelial dysfunction can be caused by intense or prolonged exposure to other damaging factors: oxygen deficiency, toxins, mediators of inflammation and allergic reactions, etc.

A variety of effects that damage the endothelium are now often called stress factors. For example, in modern fundamental cardiology, a key role in the initiation of endothelial dysfunction is played by "oxidative stress" - a process characterized by the formation inside cells of a significant amount of reactive oxygen species (superoxide anion radical, hydrogen peroxide, hydroxyl radical) that cause peroxide (free radical) oxidation lipids and proteins.

Endothelial dysfunction according to a number of generally accepted, "classical" criteria of polyetiology, monopathogeneticity, ambiguity (contradiction) of target (phenotypic) effects, corresponds to the status of a typical form of pathology of "endothelial endocrine organ".

The results of modern studies suggest that endothelial dysfunction is one of the key independent risk factors for almost all cardiovascular diseases, including coronary heart disease, atherosclerosis, primary arterial hypertension, as well as diabetes mellitus, inflammatory, autoimmune and tumor diseases. In this regard, the appearance in the medical lexicon of the concept of "endothelium-dependent diseases" was completely justified from the pathophysiological point of view. This is often referred to as the above and many other forms of pathology of modern man.

Assessment of the functional state of the endothelium

Assessment of the functional state of the endothelium. One of the key pathogenetic factors of endothelial dysfunction is a decrease in NO synthesis by endotheliocytes (see below). Hence, it seems logical to use NO as its marker. However, instability and a very short half-life (only 0.05-1.0 s) NO sharply limit! its diagnostic use in medical practice. Estimation of the content of stable NO metabolites (nitrates and nitrites) in plasma in the urine is also difficult due to the extremely high requirements for preparing a patient for such an examination. That is why the development and introduction into clinical practice of tests for assessing the severity of endothelial dysfunction was based on the perverse reaction of blood vessels to certain vasodilating stimuli.

Currently, the methods of ultrasonic assessment of vascular response (changes in blood flow velocity and/or vessel lumen diameter) in response to stimuli such as acetylcholine administration or changes in blood flow volume are most widely used.

Acetylcholine Administration Test

The introduction of acetylcholine into an intact vessel causes vasodilation (syn.: endothelium-dependent dilation) and an increase in blood flow velocity in it. Under the conditions of development of endothelial dysfunction, the vascular reaction in response to the introduction of acetylcholine becomes "perverted" (conditionally - "endothelial-independent") At the same time, the more pronounced the endothelial dysfunction in the studied vessel, the less its dilatation will be. It is even possible to develop a paradoxical reaction of the vessel, i.e. its spasm (instead of expansion), on the introduction of acetylcholine.

Test with reactive (“post-occlusive”) hyperemia (Zeler-Meyer test)

During this test, the vessel under study is subjected to short-term obturation (for example, by inflating a balloon in the lumen of the coronary artery during coronary angiography), or compression (for example, by applying a tourniquet to the brachial artery during Doppler ultrasound), and then evaluate the reaction of the vessel in response to remove obstruction to blood flow. In the "post-occlusion" period, post-ischemic arterial hyperemia should develop (dilatation of arterial vessels and an increase in the volumetric blood flow velocity). The basis of such a normal reaction is the accumulation of tissue vasodilating factors (first of all, adenosine of tissue origin) and the tonogenic effect of the blood flow itself, i.e. shear stress ("flow-dependent dilatation"). Under conditions of endothelial dysfunction, a “perverted” vascular reaction is observed, similar to that recorded during the test with acetylcholine.

In addition to these methods, a number of endothelial-produced factors of the hemostasis system are considered as potential markers of endothelial dysfunction, including procoagulants - von Willebrand factor and tissue plasminogen activator, anticoagulants - plasminogen activator inhibitor and thrombomadulin.

In 2008, a group of American scientists obtained evidence that biochemical markers of oxidative stress are an independent subject of endothelial dysfunction. In studies conducted on healthy non-smoking volunteers, they assessed endothelial function in two ways:

1) by the method of "flow-dependent vasodilation" and 2) by measuring the content of antioxidants in the participants of the experiment - tol glutagion and cysteine. At the same time, a positive correlation was established between the levels of these stress markers and flow-dependent vaedilation, which served as the basis for concluding a causal relationship between increased oxidative stress and endothelial dysfunction.

In the early 1980s, Furchgott and Zawadzki found that acetylcholine imparts vasodilation only in intact endothelium. Since that time, the level of knowledge about the functions and pathophysiology of the endothelium has risen 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 is played by nitric oxide (NO) formed in the endothelium. Nitric oxide performs an important function in the regulation of coronary blood flow, namely, it expands or narrows the lumen of the vessels in accordance with the need. An increase in blood flow, for example, during exercise, due to the shearing forces of the flowing blood, leads to mechanical irritation of the endothelium. This mechanical stimulation 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 the functions of the endothelium are normal, then the vasodilating effect of acetylcholine outweighs. When the endothelium is damaged, the balance is disturbed in the direction of vasoconstriction. This imbalance between vasodilation and vasoconstriction characterizes a condition called endothelial dysfunction. In practice, this means: intracoronary administration of acetylcholine in healthy endothelium and its normal function causes an extension 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, like a unicellular inner layer, covers the walls of blood vessels from the inside, makes it vulnerable to various influences and known cardiovascular factors risk. So, for example, with hypercholesterolemia, low-density lipoprotein cholesterol accumulates on the walls of blood vessels. Low-density lipoprotein cholesterol is oxidized, and oxygen radicals are released, 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 is understood as an increased decomposition of NO by oxygen radicals, which leads to a weakening of 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 pressure, in these cases, an increased interaction of platelets and monocytes with endothelial cells develops, and increased blood pressure also favors oxidative stress on the vessel wall, resulting in a decrease in endothelial-dependent vasodilation. With age, endothelial NO synthesis decreases and an increased reactivity of the endothelium in relation to vasoconstrictive factors develops equally. Smoking is a significant detrimental factor for endothelial function. After consumption of nicotine, doubling of circulating endothelial cells occurs in the peripheral blood, and this is a sign of an increased cell cycle and desquamation ("desquamation") of the endothelium. Already at a young age, smokers show an increased vulnerability of the endothelium and a tendency to increase endothelial dysfunction in accordance with age and the amount of nicotine consumed.

Patients with diabetes often exhibit an extremely accelerated form of arteriosclerotic changes. As its cause, endothelial dysfunction caused by chronically elevated blood sugar levels is discussed. In experimental studies, it was shown that an increased concentration of glucose leads to paradoxical vasoconstriction as a reaction to the administration of acetylcholine. Obviously, the causative role here is played not so much by a violation of NO metabolism, but by an increased formation of prostaglandins acting as vasoconstrictors, which counteract NO-transmitted vasodilation. Along with the classical risk factors for atherosclerotic vascular changes, the development of endothelial dysfunction with reduced activity of NO synthesis may also be affected by a lack of physical mobility.

Therapeutic strategies for endothelial dysfunction

The goal of therapy for endothelial dysfunction is to eliminate paradoxical vasoconstriction and, with the help of 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 the improvement of endogenous NO availability by stimulating NO synthetase or inhibiting NO breakdown (Table 1).

TO non-drug methods treatment of endothelial dysfunction include: diet therapy aimed at lowering serum cholesterol levels, systematic physical activity and refusal to consume cigarettes and alcohol. It is believed that the use of antioxidants, such as 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 endothelial-dependent vasodilation of Arteria brachialis in reactive hyperemia. Moreover, the authors discussed the capture of oxygen radicals by vitamin C as a mechanism of action and thus the better availability of NO. According to some authors, there are also reasons for the use of calcium channel blockers and replacement therapy estrogens for a positive effect on endothelial dysfunction. However, it has not yet been possible to explain the mechanism of action in detail. For a therapeutic effect on coronary tone, nitrates have long been used, which, regardless of the functional state of the endothelium, can give NO to the walls of blood vessels (Fig. 1). But although nitrates, due to the expansion of stenosed vascular segments and their hemodynamic effects, are certainly effective in reducing myocardial ischemia, they do not lead to a long-term improvement in endothelial-transmitted regulation of the vessels of the coronary vascular bed. As Harrison DG and Bates JN (1999) have established, the demand-driven rhythm of changes in vascular tone, which is controlled by endogenous NO, is not amenable to stimulation by exogenously administered NO. If you look at the impact on the cause of endothelial dysfunction, then the improvement could be achieved by reducing increased performance cholesterol and the corresponding oxidative stress in the vascular wall. And in fact, it has already been shown that after 6 months of therapy with inhibitors of coenzyme A reductase of human gonadotropic hormone, 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 as early as 6 weeks led to a functional improvement in myocardial perfusion under exercise.

The role of the reninangiotensin system (RAS) in relation to endothelial dysfunction is mainly based on the vasoconstrictor efficacy of angiotensin II. One of the first studies to show improvement in endothelial dysfunction with the ACE inhibitor quinapril was the TREND study (completed in 1996). After 6 months of therapy with quinapril, this study observed a significant improvement in paradoxical acetylcholine-mediated epicardial coronary vasoconstriction compared with patients in the placebo group. It suggests itself to count this result due to the reduced formation of angiotensin II. As an additional effect, reduced degradation of the vasodilator-acting bradykinin by inhibition of the angiotensin-converting enzyme 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 CAD 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. Is the improvement in endothelial dysfunction with human gonadotropic hormone coenzyme A reductase inhibitors and ACE inhibitors an epiphenomenon or are the beneficial effects of these two classes of substances playing a causal role in increasing life expectancy in patients with ischemic disease heart (study 4S, SOLVD, SAVE, CONSENSUS II). At present, these questions remain open.

The practical significance of endothelial dysfunction lies in understanding the imbalance between vascular protective factors and vascular damage factors. Diagnosis of endothelial damage based on paradoxical vasoconstriction, for example, with the introduction of acetylcholine, can be carried out even before the manifestation of macroscopically visible damage to the vessel. This makes it possible, especially in patients at risk, for example, with familial hypercholesterolemia or arterial hypertension, by minimizing risk factors and specific pharmacological effects (inhibitors of coenzyme A reductase of human ganadotropic hormone, ACE inhibitor, antioxidants, inhibitors of cholesterol synthesis, etc. .) defeat endothelial dysfunction or at least reduce it and maybe even improve the prognosis in such patients.

Violation of the functional state of the vascular endothelium in clinical conditions can be diagnosed by biochemical and functional markers. Biochemical markers of damaged endothelium include an increase in the blood concentration 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.

Willebrand factor (vWf) is a glycoprotein synthesized by vascular endothelial cells. Its concentration in blood plasma normally does not exceed 10 µg/ml. The von Willebrand factor is essential for the normal functioning of factor VIII in blood clotting. 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 bridges form between the surface of the subendothelium and platelets. The importance of vWf in the regulation of the hemostasis system is also confirmed by the fact that with congenital inferiority or dysfunction of this protein, a fairly often observed disease, von Willebrand's disease, develops. A number of prospective studies performed in recent years have shown that a high level of vWf in individuals with cardiovascular pathology may be important for predicting the likelihood of myocardial infarction and lethal outcome. It is believed that the level of vWf reflects the degree of damage to the vascular endothelium. Vopei et al. were the first to propose to determine the level of vWf in plasma to assess the degree of damage to the vascular endothelium. Their hypothesis was based on the fact that patients with obliterating atherosclerosis extremities or septicemia, an increased level of vWf directly reflected the extent of the vascular lesion. Subsequent studies have shown an increase in the level of vWf in various clinical conditions with damage to endothelial cells and exposure of the subendothelial layer (in hypertension, acute and chronic kidney failure, DN and vasculitis).

The data obtained in the Department of Nephropathy of the State Research Center of the Russian Academy of Medical Sciences indicate that as the severity of hypertension and diabetic kidney damage increase, 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 a vasoconstrictor of endothelial origin as a peptide consisting of 21 amino acid residues and named it endothelin. Further studies have shown 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 in the direction of the smooth muscle cells of the vascular wall. 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 potent 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 AH increases (Fig. 5.4).

adhesion molecules. Serum soluble forms of adhesive molecules are markers of activated endothelium and leukocytes (Adams, 1994). Adhesion molecules of the families of selectins and immunoglobulins (E-selectin, intercellular molecules - ICAM-1, -2, -3 and surface adhesion molecule - VCAM-1) have the greatest diagnostic significance.

E-selectin, or ELAM-1 (Eng. Endothelial Leucocyte Adhesion Molecule) is an adhesive molecule found on endothelial cells. Under the influence of damaging factors, the activated endothelium synthesizes and expresses this molecule, which creates the preconditions for subsequent receptor interaction, which is realized in the adhesion of leukocytes and platelets with the development of blood stasis.

ICAM-1 (Eng. Intercellular Adhesion Molecule, CD54) is an adhesive 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 desquamation of ICAM-1 from the membrane of ICAM-1-positive cells. The amount of serum sICAM-1 correlates with the severity of the clinical manifestations of the disease and can serve as a sign of the activity of the process.

VCAM-1 (Eng. 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, ICAM-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 DM is accompanied by an increase in the expression of adhesive molecules, indicating severe and irreversible damage to endothelial cells.

A functional marker of damaged endothelium is a violation of endothelium-dependent vasodilation of vessels, the safety of which is ensured by NO secretion. It is he who plays the role of moderator of the main functions of the endothelium. This compound regulates the activity and trigger sequence of all other biologically active substances produced by the endothelium. NO not only causes vasodilation, but also blocks the proliferation of smooth muscle cells, interferes with the adhesion of blood cells, and has antiplatelet properties. Thus, NO is the basic factor of 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 by its nature is a free radical. As a result, the favorable antiatherogenic effect of NO is leveled and inferior to the toxic atherogenic effect of other factors of the 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, an indirect and non-invasive method is used, based on the study of the response of the endothelium to various stimuli (in particular, to reactive hyperemia). This examines the change in the diameter of the brachial or radial artery (using high-resolution ultrasound Doppler) in response to its short-term clamping (5 min) 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 dilatation was obtained in studies using a specific NO inhibitor - L-NMMA, which reduced the observed dilatation effect by almost 70%. Normally, endothelium-dependent expansion of the brachial artery in response to reactive hyperemia is 8-10%. A decrease in this indicator indicates a 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 endothelial dysfunction in these patients.

Keywords

vascular endothelium / ENDOTHELIAL DYSFUNCTION/ NITRIC OXIDE / OXIDATIVE STRESS/ VASCULAR ENDOTHELIUM / ENDOTHELIAL DYSFUNCTION / NITRIC OXIDE / OXIDATIVE STRESS

annotation scientific article on clinical medicine, author of scientific work - Melnikova Yulia Sergeevna, Makarova Tamara Petrovna

The vascular endothelium is a unique "endocrine tree" that lines absolutely all organs of the vascular system of the body. Endothelial cells create a barrier between blood and tissues, perform a number of important regulatory functions, synthesizing and releasing a large number of various biologically active substances. The strategic location of the endothelium allows it to be sensitive to changes in the hemodynamic system, signals carried by the blood, and signals from the underlying tissues. A balanced release of biologically active substances contributes to the maintenance of homeostasis. To date, data have been accumulated on the versatility of the mechanisms of participation of the endothelium in the occurrence and development of various pathological conditions. This is due not only to its participation in the regulation of vascular tone, but also to its direct influence on the processes of atherogenesis, thrombosis, and protection of the integrity of the vascular wall. endothelial dysfunction considered as a pathological condition of the endothelium, which is based on a violation of the synthesis of endothelial factors. As a result, the endothelium is not able to provide hemorheological balance of blood, which leads to dysfunction of organs and systems. Endothelial dysfunction a key link in the pathogenesis of many diseases and their complications. At present, the role of endothelial dysfunction in the development of such chronic diseases as atherosclerosis, arterial hypertension, chronic heart failure, diabetes mellitus, chronic obstructive pulmonary disease, chronic kidney disease, inflammatory diseases intestines, etc. The review presents data on the functions and dysfunction of the vascular endothelium. Forms Considered endothelial dysfunction. Modern concept introduced endothelial dysfunction as a central link in the pathogenesis of many chronic diseases. Endothelial dysfunction precedes the development of clinical manifestations of diseases, therefore, it seems promising to study the state of the endothelium on early stages development of diseases, which is of great diagnostic and prognostic value.

Endothelial dysfunction as the key link of chronic diseases pathogenesis

Endothelium is the unique "endocrine tree" lining absolutely all cardiovascular system organs of the body. Endothelial cells form a barrier between the blood and tissues, perform a number of important regulatory functions, synthesizing and releasing a wide range of biologically active substances. The strategic location of the endothelium allows it to be sensitive to haemodynamic changes as well as to the signals carried by the blood and signals of underlying tissues. Balanced release of biologically active substances contributes to homeostasis maintenance. The data concerning the multiple mechanisms of endothelium participation in the origin and development of various pathological conditions is accumulated so far. This is not only due to its participation in vascular tone regulation, but also due to the direct influence on atherogenesis, thrombus formation, and protection of the vascular wall integrity. Endothelial dysfunction is considered as a pathological condition of the endothelium based on impaired synthesis of endothelial factors. As a result, endothelium is unable to provide the haemorheological balance of the blood, resulting in disorders of different organs and systems functions. Endothelial dysfunction is a key link in the pathogenesis of many diseases and their complications. The role of endothelial dysfunction in the development of chronic diseases such as atherosclerosis, arterial hypertension, chronic heart failure, diabetes mellitus, chronic obstructive pulmonary disease, chronic kidney disease, inflammatory bowel disease, and others has been proven recently. The provides review data on the functions of vascular endothelium and its dysfunction. Types of endothelial dysfunction are described. Modern concept of endothelial dysfunction as the key link of pathogenesis of many chronic diseases is presented. Endothelial dysfunction precedes the development of clinical manifestations of diseases, so the study of the endothelium condition at early stages of the diseases is promising and could be of great diagnostic and prognostic value.

The text of the scientific work on the topic "Endothelial dysfunction as a central link in the pathogenesis of chronic diseases"

child, lead to increased shortness of breath, tachycardia, cyanosis, the appearance of hypoxic attacks and attacks of paroxysmal tachycardia.

3. Parents of a child with chronic heart failure should have all useful information about this problem and actively promote the achievement of optimal results in treatment, improve prognosis, and increase the life expectancy of children.

financial support/conflict of interest to be disclosed.

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ENDOTHELIAL DYSFUNCTION AS A CENTRAL LINK IN THE PATHOGENESIS OF CHRONIC DISEASES

Yulia Sergeevna Melnikova *, Tamara Petrovna Makarova Kazan State Medical University, Kazan, Russia

Abstract DOI: 10.17750/KMJ2015-659

The vascular endothelium is a unique "endocrine tree" that lines absolutely all organs of the vascular system of the body. Endothelial cells create a barrier between blood and tissues, perform a number of important regulatory functions, synthesizing and releasing a large number of various biologically active substances. The strategic location of the endothelium allows it to be sensitive to changes in the hemodynamic system, signals carried by the blood, and signals from the underlying tissues. A balanced release of biologically active substances contributes to the maintenance of homeostasis. To date, data have been accumulated on the versatility of the mechanisms of participation of the endothelium in the occurrence and development of various pathological conditions. This is due not only to its participation in the regulation of vascular tone, but also to its direct influence on the processes of atherogenesis, thrombosis, and protection of the integrity of the vascular wall. Endothelial dysfunction is considered as a pathological condition of the endothelium, which is based on a violation of the synthesis of endothelial factors. As a result, the endothelium is not able to provide hemorheological balance of blood, which leads to dysfunction of organs and systems. Endothelial dysfunction is a key link in the pathogenesis of many diseases and their complications. At present, the role of endothelial dysfunction in the development of such chronic diseases as atherosclerosis, arterial hypertension, chronic heart failure, diabetes mellitus, chronic obstructive pulmonary disease, chronic kidney disease, inflammatory bowel disease, etc. has been proven. The review provides data on the functions and dysfunction of the vascular endothelium. Forms of endothelial dysfunction are considered. The modern concept of endothelial dysfunction as a central link in the pathogenesis of many chronic diseases is presented. Endothelial dysfunction precedes the development of clinical manifestations of diseases; therefore, it seems promising to study the state of the endothelium in the early stages of disease development, which is of great diagnostic and prognostic value.

Key words: vascular endothelium, endothelial dysfunction, nitric oxide, oxidative stress.

ENDOTHELIAL DYSFUNCTION AS THE KEY LINK OF CHRONIC DISEASES PATHOGENESIS

Yu.S. Mel "nikova, T.P. Makarova

Kazan State Medical University, Kazan, Russia

Address for correspondence: [email protected]

Keywords: vascular endothelium, endothelial dysfunction, nitric oxide, oxidative stress.

The problem of endothelial dysfunction is currently attracting many researchers, since it is one of the predictors of morphological changes in the vascular wall in atherosclerosis, arterial hypertension, diabetes, chronic disease kidneys, etc. Endothelial dysfunction in this case, as a rule, is systemic in nature and is found not only in large vessels, but also in the microvasculature.

The vascular endothelium, by classical definition, is a single layer of flat cells of mesenchymal origin, lining the inner surface of blood and lymphatic vessels, as well as cardiac cavities. According to modern concepts, the endothelium is not just a semipermeable membrane, but an active endocrine organ, the largest in the human body. A large area of vessels, their penetration into all organs and tissues create the prerequisites for the spread of endothelial influences on all organs, tissues and cells.

Vascular endothelium has long been considered a protective layer, a membrane between the blood and the inner membranes of the vessel wall. And only at the end of the twentieth century, after the award to a group of scientists consisting of R. Furchgott, L.S. Ignorro, F. Murad in 1998 Nobel Prize in Medicine for studying the role of nitric oxide as a signaling molecule of the cardiovascular system, it became possible to explain many processes of regulation of the cardiovascular system in normal and pathological conditions. This opened up a new direction in fundamental and clinical research participation of the endothelium in the pathogenesis of arterial hypertension and other cardiovascular diseases, as well as ways to effectively correct its dysfunction.

The most important functions of the endothelium are the maintenance of hemovascular homeostasis, the regulation of hemostasis, the modulation of inflammation, the regulation of vascular tone and vascular permeability. In addition, endothelium was found to have its own

naya renin-angiotensin system. The endothelium secretes mitogens, participates in angiogenesis, fluid balance, and the exchange of components of the extracellular matrix. These functions are performed by the vascular endothelium through the synthesis and release of a large number of various biologically active substances (Table 1).

The main task of the endothelium is the balanced release of biologically active substances that determine the holistic work of the circulatory system. There are two options for the secretion of biologically active substances by the endothelium - basal, or constant, and stimulated secretion, that is, the release of biologically active substances during stimulation or damage to the endothelium.

The main factors stimulating the secretory activity of the endothelium include changes in blood flow velocity, circulating and/or intraparietal neurohormones (catecholamines, vasopressin, acetylcholine, bradykinin, adenosine, histamine, etc.), platelet factors (serotonin, adenosine diphosphate, thrombin) and hypoxia. Risk factors for endothelial damage include hypercholesterolemia, hyperhomocysteinemia, elevated levels of cytokines (interleukins-1p and -8, tumor necrosis factor alpha).

By the rate of formation of various factors in the endothelium (which is largely due to their structure), as well as by the predominant direction of secretion of these substances (intracellular or extracellular), substances of endothelial origin can be divided into the following groups.

1. Factors that are constantly formed in the endothelium and released from cells in the basolateral direction or into the blood (nitric oxide, prostacyclin).

2. Factors that accumulate in the endothelium and are released from it during stimulation (von Willebrand factor, tissue plasminogen activator). These factors can enter the blood not only when the endothelium is stimulated, but also when it is activated and damaged.

Table 1

Factors synthesized in the endothelium and determining its functions

Factors affecting vascular smooth muscle tone

Vasoconstrictors Vasodilators

Endothelin Nitric Oxide

Angiotensin II Prostacycline

Thromboxane A2 Endothelin depolarization factor

Prostaglandin H2 Angiotensin I Adrenomedulin

Hemostasis factors

Prothrombogenic Antithrombogenic

Platelet Growth Factor Nitric Oxide

Tissue plasminogen activator inhibitor Tissue plasminogen activator

Willebrand factor (VW clotting factor) Prostacycline

Angiotensin IV Thrombomodulin

Endothelin I

fibronectin

Thrombospondin

Platelet activating factor (PAF)

Factors affecting growth and proliferation

Stimulants Inhibitors

Endothelin I Nitric Oxide

Angiotensin II Prostacycline

Superoxide radicals C-type natriuretic peptide

Endothelial growth factor Heparin-like growth inhibitors

Factors affecting inflammation

Pro-inflammatory Anti-inflammatory

Tumor necrosis factor alpha Nitric oxide

superoxide radicals

C-reactive protein

3. Factors, the synthesis of which practically does not occur under normal conditions, but increases sharply with the activation of the endothelium (endothelin-1, type 1 intercellular adhesion molecule - ICAM-1, type 1 vascular endothelial adhesion molecule - UCAM-1).

4. Factors synthesized and accumulated in the endothelium (tissue plasminogen activator - 1-PA) or which are membrane proteins (receptors) of the endothelium (thrombomodulin, protein C receptor).

In a physiological state, the endothelium has the ability to maintain a balance

between its multidirectional functions: the synthesis of pro- and anti-inflammatory factors, vasodilating and vasoconstrictive substances, pro- and anti-aggregants, pro- and anticoagulants, pro- and antifibrinolytics, proliferation factors and growth inhibitors. Under physiological conditions, vasodilation, the synthesis of inhibitors of aggregation, coagulation and fibrinolysis activators, anti-adhesive substances predominate. Vascular cell dysfunction disrupts this balance and predisposes vessels to vasoconstriction, leukocyte adhesion, platelet activation, mitogenesis, and inflammation.

Thus, endothelial function is a balance of opposing principles: relaxing and constrictive factors, anticoagulant and procoagulant factors, growth factors and their inhibitors.

Such causes as impaired blood flow, hypoxia, increased systemic and intrarenal pressure, hyperhomocysteinemia, and increased lipid peroxidation processes can lead to a change in the physiological balance in the body. The vascular endothelium is extremely vulnerable, but, on the other hand, researchers note its enormous compensatory capabilities in violation of physiological conditions.

Endothelial dysfunction was first described in 1990 on the vessels of the human forearm in hypertension and was defined as impaired vasodilation upon the action of specific stimuli such as acetylcholine or bradykinin. More broad understanding The term includes not only a decrease in vasodilation, but also a proinflammatory and prothrombotic state associated with endothelial dysfunction. Mechanisms involved in the reduction of vasodilatory responses in endothelial dysfunction include decreased nitric oxide synthesis, oxidative stress, and decreased hyperpolarizing factor production.

Currently, endothelial dysfunction is understood as an imbalance between the formation of vasodilating, athrombogenic, antiproliferative factors, on the one hand, and vasoconstrictive, prothrombotic and proliferative substances synthesized by the endothelium, on the other. Endothelial dysfunction can be an independent cause of circulatory disorders in the organ, since it often provokes angiospasm or vascular thrombosis. On the other hand, regional circulation disorders (ischemia, venous stasis) can also lead to endothelial dysfunction. Hemodynamic causes, age-related changes, free radical damage, dyslipoproteinemia, hypercytokinemia, hypothyroidism can contribute to the formation of endothelial dysfunction.

perhomocysteinemia, exogenous and endogenous intoxications. Endothelial dysfunction can lead to structural damage in the body: accelerated apoptosis, necrosis, de-squamation of endotheliocytes. However, functional changes in the endothelium usually precede morphological changes in the vascular wall.

There are four forms of endothelial dysfunction: vasomotor, thrombophilic, adhesive and angiogenic.

The vasomotor form of endothelial dysfunction is caused by a violation of the ratio between endothelial vasoconstrictors and vasodilators and is important in the mechanisms of both systemic increase blood pressure and local angiospasm. Some of the vasoactive substances produced by the endothelium cannot be clearly classified as vasodilators or vasoconstrictors, due to the existence of several types of receptors for these substances. Some types of receptors mediate vasoconstrictive reactions, others - vasodilators. Sometimes activation of receptors of the same type, located on endothelial and smooth muscle cells of blood vessels, gives opposite results. According to the principle of antagonistic regulation, the formation of vasoconstrictive substances, as a rule, is associated with stimulation of the synthesis of vasodilators.

The resulting effect (vasoconstrictor or vasodilator) of vasoactive substances depends on their concentration, as well as the type and localization of vessels, which is explained by the uneven distribution of receptors in arteries, arterioles, venules, and even in vessels of the same type in different regions.

The thrombophilic form of endothelial dysfunction is caused by a violation of the ratio of thrombogenic and athrombogenic substances formed in the endothelium and participating in hemostasis or affecting this process. Under physiological conditions, the formation of athrombogenic substances in the endothelium prevails over the formation of thrombogenic ones, which ensures the preservation of the liquid state of the blood in case of damage to the vascular wall. The thrombophilic form of endothelial dysfunction can lead to the development of vascular thrombophilia and thrombosis. A significant decrease in vascular thromboresistance occurs with atherosclerosis, arterial hypertension, diabetes mellitus, and tumor diseases.

The adhesive form of endothelial dysfunction is caused by a violation of the interaction between leukocytes and the endothelium - a constantly ongoing physiological process that is carried out with the participation of special adhesive molecules. On the luminal surface of endotheliocytes, P- and E-selectins, adhesion molecules (ICAM-1, 662

VCAM-1). Expression of adhesion molecules occurs under the influence of inflammatory mediators, anti-inflammatory cytokines, thrombin, and other stimuli. With the participation of P- and E-selectins, the delay and incomplete stop of leukocytes are carried out, and ICAM-1 and VCAM-1, interacting with the corresponding ligands of leukocytes, ensure their adhesion. Increased adhesiveness of the endothelium and uncontrolled adhesion of leukocytes have great importance in the pathogenesis of inflammation in atherosclerosis and other pathological processes.

The angiogenic form of endothelial dysfunction is associated with a violation of neoangiogenesis, a process in which several stages are distinguished: an increase in endothelial permeability and destruction of the basement membrane, migration of endothelial cells, proliferation and maturation of endothelial cells, and vascular remodeling. At various stages of angiogenesis, factors formed in the endothelium play an extremely important role: vascular endothelial growth factor (VEGF), endothelial growth factor (EGF), in addition, there are receptors on the endothelial surface that interact with angiogenesis regulators (angiopoietins, angiostatin, vasostatin, etc.), formed in other cells. Dysregulation of neoangiogenesis or stimulation of this process, out of connection with functional needs, can lead to serious consequences.

The modern understanding of endothelial dysfunction, according to Russian scientists, can be reflected in the form of three complementary processes: a shift in the balance of antagonist regulators, a violation of reciprocal interactions in feedback systems, the formation of metabolic and regulatory "vicious circles" that change functional state of endothelial cells, which leads to dysfunction of tissues and organs.

Endothelial dysfunction as a typical pathological process is a key link in the pathogenesis of many diseases and their complications.

With prolonged exposure to damaging factors on the endothelium (such as hypoxia, toxins, immune complexes, inflammatory mediators, hemodynamic overload, etc.), endothelial cells are activated and damaged, subsequently leading to a pathological response even to ordinary stimuli in the form of vasoconstriction, thrombosis - development, increased cell proliferation, hypercoagulability with intravascular fibrinogen deposition, impaired microhemorheology. The longer the pathological response to irritating stimuli persists, the faster the chronization of the process and the stabilization of irreversible phenomena occur. Thus, chronic activation of the endothelium can lead to the formation of a "vicious circle"

and endothelial dysfunction.

Decreased endothelial synthesis of nitric oxide (NO), increased levels of endothelin-1, circulating von Willebrand factor, plasminogen activator inhibitor, homocysteine, thrombomodulin, soluble molecule of vascular intercellular adhesion B1, C-reactive protein, microalbuminuria and etc. .

To date, data have been accumulated on the versatility of the mechanisms of participation of the endothelium in the emergence and development of various pathological conditions.

The main role in the development of endothelial dysfunction is played by oxidative stress, the synthesis of powerful vasoconstrictors, as well as cytokines and tumor necrosis factor, which suppress the production of nitric oxide (NO).

Oxidative (oxidative) stress is one of the most widely studied mechanisms of endothelial dysfunction. Oxidative stress is defined as an imbalance between excess formation free radicals and lack of antioxidant defense mechanisms. Oxidative stress is an important pathogenetic link in the development and progression of various diseases. The participation of free radicals in the inactivation of nitric oxide and the development of endothelial dysfunction has been proven.

Oxidation is an important process for life, and hydrogen peroxide, as well as free radicals such as superoxide, hydroxyl radical and nitric oxide, are constantly formed in the body. Oxidation becomes a powerful damaging factor only with excessive formation of free radicals and / or a violation of antioxidant protection. Products of lipid peroxidation damage endothelial cells by initiating radical chain reactions in membranes. The triggering mediator of oxidative stress in the vascular bed is NADH/NADPH oxidase of the cytoplasmic membrane of macrophages, which produces superoxide anions. In addition, in the presence of hypercholesterolemia in the vascular wall, the formation of NO decreases due to the accumulation of NO-synthase inhibitors, such as L-glutamine, asymmetric dimethylarginine, as well as a decrease in the concentration of the NO-synthase cofactor - tetrahydrobiopterin.

NO is synthesized from L-arginine in the presence of a number of cofactors and oxygen by various isoforms of NO synthase (NOS): neuronal or cerebral (nNOS), inducible (iNOS), and endothelial (eNOS). For biological activity, not only the amount, but also the source of NO is important. Nitric oxide synthesized in the endothelium diffuses into vascular smooth muscle cells and stimulates soluble guanylate cyclase there. This leads to

an increase in the content of cyclic guanosine monophosphate (cGMP) in the cell, the calcium concentration in smooth muscle cells decreases, resulting in relaxation of vascular smooth muscle cells and vasodilation.

Nitric oxide is released by endothelial cells and is a chemically unstable compound that exists for several seconds. In the vessel lumen, NO is quickly inactivated by dissolved oxygen, as well as by superoxide anions and hemoglobin. These effects prevent NO from acting at a distance from its release site, making nitric oxide an important regulator of local vascular tone. Impaired or absent NO synthesis due to endothelial dysfunction cannot be compensated for by its release from healthy borderline endothelial cells. It is now known that of the large number of biologically active substances secreted by the endothelium, it is nitric oxide that regulates the activity of other mediators.

There is a correlation between markers of oxidative stress and endothelial dysfunction. Endothelial dysfunction may result from a decrease in the ability of the endothelium to synthesize, release, or inactivate NO.

Of interest is the reaction of interaction of nitric oxide with superoxide anion with the formation of peroxynitrite, which is not a vasodilator, and then peroxynitrous acid, which is converted into nitrogen dioxide and a particularly active hydroxyl radical. The result of this reaction, firstly, is a violation of endothelium-dependent vasodilation, which is accompanied by insufficient perfusion of organs, and secondly, the hydroxyl radical has a powerful damaging effect on cells and exacerbates inflammation.

Thus, the vascular endothelium is an active dynamic structure that controls many important body functions. At present, ideas about the functions of the endothelium have expanded significantly, which allows us to regard the vascular endothelium not only as a selective barrier to the penetration of various substances from the bloodstream into the interstitium, but also as a key link in the regulation of vascular tone. The main lever of influence of the endothelium is the release of a number of biologically active substances.

To date, the concept of endothelial dysfunction has been formulated as a central link in the pathogenesis of many chronic diseases. The main role in the development of endothelial dysfunction is played by oxidative stress, the synthesis of powerful vasoconstrictors that inhibit the formation of nitric oxide. Endothelial dysfunction precedes

the development of clinical manifestations of diseases, therefore, the evaluation of endothelial functions is of great diagnostic and prognostic value. Further study of the role of endothelial dysfunction in the development of diseases is necessary for the development of new therapeutic approaches.

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UDC 616.12-008.331.1-053.2: 612.172: 612.181: 612.897

THE ROLE OF THE SEROTONINERGIC SYSTEM IN THE DEVELOPMENT OF DISEASES

HEART AND VESSELS IN CHILDREN

Dinara Ilgizarovna Sadykova1, Razina Ramazanovna Nigmatullina2, Gulfiya Nagimovna Aflyatumova3*

Kazan State Medical Academy, Kazan, Russia;

Kazan State Medical University, Kazan, Russia;

3Children's Republican clinical Hospital, Kazan, Russia

Abstract DOI: 10.17750/KMJ2015-665

In recent decades, the role of the serotonin system as a link in the pathogenesis of atherosclerosis and arterial hypertension has been widely discussed. Serotonin and histamine are a humoral system of regulators and modulators of physiological processes, which, under conditions of pathology, turn into factors contributing to the development of the disease. Membrane serotonin transporter has been identified on neurons, platelets, myocardium and smooth muscle cells. The higher the activity of the membrane carrier, the higher the concentration of serotonin in platelets, its release into the blood plasma increases and its negative effects on platelets and the vessel wall are realized. The 5-HT1A, 5-HT2, and 5-HT3 receptor subtypes play a key role in the central mechanisms of regulation of cardiovascular activity, while the peripheral effects of serotonin on the vascular system are mediated by the 5-HT1, 5-HT2, 5-HT3, 5-HT4, and 5-HT7. Activation of 5-HT1A receptors causes central inhibition of sympathetic influences and further bradycardia, while 5-HT2 receptors cause excitation of the sympathetic division, increased blood pressure, and tachycardia. With the development of anaerobic processes, serotonin through 5-HT2 receptors triggers the process of apoptosis of cardiomyocytes, which leads to the development and progression of heart failure. The participation of 5HT2B receptors in the regulation of heart development during embryogenesis was proven in mice mutant for this receptor: cardiomyopathy was noted with loss of ventricular mass due to a decrease in the number and size of cardiomyocytes. The participation of 5-HT4 receptors in the development of sinus tachycardia and atrial fibrillation has been shown, in turn, the use of 5-HT4 receptor antagonists has been effective in the treatment this violation rhythm. Thus, the study of the role of the serotonergic system in the development of cardiovascular diseases will reveal new links in the pathogenesis of arterial hypertension in childhood.

Keywords: serotonergic system, cardiovascular diseases, arterial hypertension,

THE ROLE OF SEROTONERGIC SYSTEM IN CARDIOVASCULAR DISEASES DEVELOPMENT IN CHILDREN

D.I. Sadykova1, R.R. Nigmatullina2, G.N. Aflyatumova3

Kazan State Medical Academy, Kazan, Russia;

2Kazan State Medical University, Kazan, Russia;

3Children's Republican Clinical Hospital, Kazan, Russia

The role of the serotonin system as a link in the pathogenesis of atherosclerosis and arterial hypertension is widely discussed during the recent decades. Serotonin and histamine are part of the humoral system of physiological processes regulators and modulators which under pathological conditions are transformed into factors contributing to the disease development. The membrane serotonin transporter has been identified on neurons, platelets, myocardium and smooth muscle cells. The higher is the activity of membrane transporter, the higher is the platelet serotonin concentration, its release into the blood plasma increases thus implementing its negative effects on platelets and wall of the vessels. 5-HT1A, 5-HT2 and 5-HT3 receptor subtypes play a key role in the central mechanisms of regulation of cardiovascular activities while peripheral effects of serotonin on the vascular system are mediated by 5-HT1, 5-HT2, 5-HT3, 5-HT4 and 5-HT7 receptor subtypes. Activation of 5-HT1A receptors causes inhibition of central sympathetic influences and further bradycardia, while 5-HT2 receptors activation - arousal of the sympathetic division, blood pressure elevation, and tachycardia. With the development of anaerobic processes serotonin via 5-HT2 receptors triggers apoptosis of cardiomyocytes leading to the development and progression of heart failure. Participation of 5HT2B receptors in the regulation of heart development during embryogenesis

Address for correspondence: [email protected]

Endothelial dysfunction implies a functional lesion of the endothelium - a layer of cells lining the lumen of all blood vessels. These cells, highlighting various factors, respond to mechanical (primarily hemodynamic) effects and chemicals contained in the blood. In addition to the properties described above, the endothelium has a barrier function between blood and tissues, controlling the transport of various substances between them. And most importantly, the endothelium determines the anatomical and functional state of the vessels. Endothelial dysfunction leads to a violation of this condition, the end result of which is a decrease in the relaxing function of vascular smooth muscle cells, which contributes to pathological vasoconstriction, followed by the start of processes leading to atherosclerotic lesions. However, almost all researchers believe that erectile dysfunction can not only be a manifestation of a somatic disease, but also be an independent disease. The same researchers proved that erectile dysfunction precedes the early manifestations of atherosclerotic lesions of large vessels.

It should be taken into account that in a certain part of the patients who were diagnosed with atherosclerotic lesions of large vessels, during the onset of erectile disorders, there was no organic narrowing of the internal genital and cavernous arteries, small in diameter. From which it follows that arteriogenic ED is not always associated with atherosclerotic lesions of the cavernous arteries, and may be due to endothelial dysfunction. This assumption is proved by recent studies that have shown the possibility of restoring erection in some patients after the elimination of risk factors, as well as after drug therapy. The high efficiency of PDE-5 inhibitors, as well as vasoactive drugs for intracavernous administration, exceeding 70% for the period of action of the drugs and leading to partial or complete restoration of erectile function, also does not agree with the data of therapy for atherosclerosis of large vessels.

Therefore, despite the violation of the functional properties of endothelial cells arising from damage to the cavernous arteries, accompanied by the destruction of these cells and their incomplete regeneration, when risk factors are eliminated, erection restoration in some patients.

The data presented show that in The basis of arteriogenic erectile dysfunction in some patients is not organic, but functional, potentially reversible damage to the arteries .

In recent years, overwhelming evidence has been obtained that NO is an important component in the protection of endothelial function. Hedlund and Aszodi found that accidental damage to the endothelium leads to the loss of the ability of the vessels to relax under the action of acetylcholine, and suggested that some unstable factor is probably released from the endothelium, which they called the endothelial relaxation factor, which they identified as NO. Apart from this important function, the role of NO in the penis is very complex and involves the regulation of the biochemical mechanism of erection.

Thus, NO is a substance that is constantly produced and secreted by autonomic nerve endings and endothelial cells into the cavernous tissue. Synthesis of NO in the body is carried out as a result of 5-electron oxidation of the terminal nitrogen atom of guanidine of the amino acid L-arginine using a family of enzymes defined as NO synthases (NOS) and belonging to the class of heme-containing cytoreductases similar to cytochrome P-450.

Assessing the role of NO in penile erection, the main attention is paid to its constitutive - endothelial and neural sources, which are functionally associated with the plasma membrane, are constantly expressed and provide basal release of NO.

There is also an inducible NO-synthetase, the so-called macrophage, formed in leukocytes, the function of which is limited in their cytotoxic action. While the endothelial and neural isoforms are constitutional variants of the enzyme, inducible NO synthetase is expressed mainly during inflammation or infection.

NO produced by endothelial cells and non-cholinergic non-adrenergic nerve endings of the cavernous bodies of the penis, by relaxing the smooth muscle cells of the arteries and trabeculae, provides an increase in arterial blood flow, followed by an increase in intracavernous pressure and the development of an erection of the penis. The systemic process leading to a decrease in the ability of the endothelium to synthesize and release nitric oxide NO, as well as a decrease in the bioavailability of the latter, is the direct cause of the development of erectile dysfunction.

Formed in nerve fibers and endothelium, NO passes into vascular smooth muscle cells, stimulating dissolved guanyline cyclase, which leads to an increase in cGMP levels by converting guanosine triphosphate to cyclic guanosine monophosphate.

The classic regulatory role of cGMP is to stimulate muscle cell relaxation, degranulation of neutrophils, and inhibition of platelet aggregation. The study of NO\cGMP-mediated relaxation clearly showed that the trigger in the cascade of reactions is cyclic guanosine monophosphate-dependent kinase I, which reduces intracellular calcium concentration as a result of inhibition of calcium channel activity and the opening of Ca2+-dependent K+ channels, leading to hyperpolarization and disruption phosphorization of light chains of smooth muscle cells. The mediator blocking the physiological action of cyclic guanosine monophosphate is an enzyme from the phosphodiesterase family, which, by hydrolysis of the 3"5" bond, leads to a break in this chain.

The cause of nitrous oxide deficiency in the endothelium can be: a decrease in the production of endothelial NO, its rapid oxidation by an excess of free radicals, an increase in the production of endothelial vasoconstrictor factors that counteract the vasodilatory effect of NO or mask it. It should also be taken into account that the NO molecule itself is unstable and its lifetime is about 10 sec. The expression of NO-synthetase can vary within certain limits, being directly dependent on the concentration of L-arginine. A decrease in its intracellular concentration due to a deterioration in the transport of L-arginine to endothelial cells, as well as an increase in the activity of the arginase enzyme that breaks down arginine, can disrupt the function of endothelial NO synthetase and also lead to endothelial dysfunction. These data explain the high competitive effectiveness of L-arginine in the correction of endothelial dysfunction.

It is also known that the level of eNO-synthetase decreases when exposed to endothelial. cells of mediators - inflammation and low density lipoproteins. It is important to take into account the disruption of the structure of NO-synthetase by inhibiting this enzyme with endogenous inhibitors N-monomethylarginine and asymmetric dimethylarginine. . This process, as well as a decrease in the concentration of tetrahydrobiopterin, occurs mainly in various pathological conditions, including hypercholesterolemia,. hypertension, peripheral atherosclerosis and cardiac; insufficiency.

Finally, the response of smooth muscle to NO may change at the level of ion channels or receptors. Apparently, a decrease in the sensitivity of smooth muscle cell receptors to NO is not significant reason development of endothelial dysfunction; which is proved by the preserved vascular response to the use of nitrates in patients with severe endothelial dysfunction. . It should also be noted that in endothelial NO synthetase, the Ca2+-calmodulin complex is, as it were, a subunit of the enzyme, and therefore the activity of this NOS subtype depends on changes in the concentration of intracellular calcium.

More recently, potential risk factors for atherosclerosis have been homocysteinemia. Homocysteine is a sulfur-containing amino acid formed during the metabolism of methionine.

Homocysteine leads to endothelial. dysfunction by weakening vascular tone and blood flow in them, activation and adhesion of inflammatory cells, mitogenic effect on smooth muscle cells, stimulating the accumulation of proteins in atheroma and collagen biosynthesis, as well as by weakening the antithrombotic function of endothelial cells. An increase in the concentration of homocysteine in the blood leads to the creation of conditions for the development and progression of atherosclerosis, which are realized through several mechanisms.

In blood plasma, homocysteine is easily oxidized to form homocystin, mixed disulfides of homocysteine and homocysteine-thiolactone, which are toxic to endothelial cells.

Homocysteine promotes the formation of disulfide derivatives of proteins, the accumulation in cell membranes and the intercellular space of low density lipoproteins (LDL) and very low density lipoproteins (VLDL) and their oxidation, as well as a decrease in the synthesis of sulfur-containing glycosaminoglycans, which leads to a decrease in the elasticity of vessel walls. As a result, the vessels lose their elasticity, their ability to dilate decreases, which is largely due to dysfunction: endothelium.

Thus, an excess of homocysteine in the body creates problems: it is the first to be introduced into the endothelium of the vessels, and damage it, and only then "cholesterol" is taken "to work".

Homocysteine also affects another link in the pathogenesis of atherosclerosis - thrombogenesis. There is evidence in the literature that homocysteine increases the aggregation ability of platelets and their adhesive properties, disrupts the function of tissue plasminogen activator, blocking: its binding to endotheliocytes, stimulates coagulation factors - V, X and XII, and also inhibits the function of natural anticoagulants, such as antithrombin III and protein C, increasing thrombin activity.

The severity of homocysteinemia correlates with the risk of developing ED, established a significant relationship between the level of homocysteine and the severity of ED

Homocysteine leads to inhibition of the effects of nitric oxide, reduces its bioavailability, affects the sensitivity of tissues to it. D. Lang, M. Kredan et al. expressed an opinion on the relationship of homocysteine with the production of nitric oxide (NO) through NO synthase, which made it possible to explain the mechanism of endothelial dysfunction.

The results obtained confirm the data on atherosclerosis as a diffuse process in which endothelial dysfunction initiated by risk factors manifests itself in both systemic and peripheral arteries. Vascular remodeling and endothelial dysfunction are interrelated aspects of the same process.

Plasma homocysteine levels tend to increase with age, especially in individuals with arterial hypertension and hypercholesterolemia, which is associated with age-related physiological changes.

Thus, the results of the above study confirm the hypothesis that endothelial dysfunction precedes atherosclerosis, since there is a clear relationship between endothelial-dependent vasodilation disorders and risk factors and the possibility of restoring it after their correction. decline advanced level homocysteine, LDL cholesterol and improvement of endothelial function is a priority in the secondary prevention of coronary artery disease. It should be taken into account that, regardless of the predominance of certain mechanisms for the development of endothelial dysfunction, they are interrelated.

Summarizing the data on the pathogenesis of endothelial dysfunction, it can be assumed that all of the above mechanisms may be involved to varying degrees in its development in various diseases, emphasizing the role of endothelial disorders as the main pathological process resulting from the action of unfavorable factors on the vessels. Elucidation of the exact cause of endothelial dysfunction is very important for the development of targeted therapies for arteriogenic erectile dysfunction.

Gasanov R.V. Influence of Regulatory Administration of Type 5 Phosphodiesterase Inhibitors on Erectile and Endothelial Functions in Patients with Arteriogenic Erectile Dysfunction

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