Endothelial dysfunction fundamental and clinical aspects. Endothelial dysfunction: manifestations, examinations, treatment. Who should be screened for endothelial dysfunction?

H What causes the development of metabolic syndrome and insulin resistance (IR) of tissues? What is the relationship between IR and the progression of atherosclerosis? These questions have not yet received a clear answer. It is assumed that the primary defect underlying the development of IR is dysfunction of vascular endothelial cells.

The vascular endothelium is a hormonally active tissue, which is conditionally called the largest human endocrine gland. If all endothelial cells are isolated from the body, their weight will be approximately 2 kg, and the total length will be about 7 km. The unique position of endothelial cells at the border between circulating blood and tissues makes them the most vulnerable to various pathogenic factors in the systemic and tissue circulation. It is these cells that are the first to meet with reactive free radicals, with oxidized low-density lipoproteins, with hypercholesterolemia, with high hydrostatic pressure inside the vessels lined by them (with arterial hypertension), with hyperglycemia (with diabetes mellitus). All these factors lead to damage to the vascular endothelium, dysfunction of the endothelium as an endocrine organ, and accelerated development of angiopathy and atherosclerosis. The list of endothelial functions and their disorders are listed in Table 1.

Functional restructuring of the endothelium under the influence of pathological factors goes through several stages:

I stage - increased synthetic activity of endothelial cells, the endothelium works as a “biosynthetic machine”.

II stage - violation of the balanced secretion of factors that regulate vascular tone, hemostasis system, processes of intercellular interaction. At this stage, the natural barrier function of the endothelium is disrupted, and its permeability to various plasma components increases.

III stage - depletion of the endothelium, accompanied by cell death and slow processes of endothelial regeneration.

Of all the factors synthesized by the endothelium, the role of the “moderator” of the main functions of the endothelium belongs to the endothelial relaxation factor or nitric oxide (NO). It is this compound that regulates the activity and sequence of “launching” of all other biologically active substances produced by the endothelium. Nitric oxide not only causes vasodilation, but also blocks the proliferation of smooth muscle cells, prevents the adhesion of blood cells and has antiplatelet properties. Thus, nitric oxide is the basic factor of antiatherogenic activity.

Unfortunately, it is the NO-producing function of the endothelium that 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 gives way to the toxic atherogenic effect of other factors of the damaged endothelium.

Currently There are two points of view on the cause of endotheliopathy in metabolic syndrome. . Proponents of the first hypothesis argue that endothelial dysfunction is secondary to the existing IR, i.e. is a consequence of those factors that characterize the state of IR - hyperglycemia, arterial hypertension, dyslipidemia. Hyperglycemia in endothelial cells activates the protein kinase-C enzyme, which increases the permeability of vascular cells for proteins and disrupts endothelium-dependent vascular relaxation. In addition, hyperglycemia activates the processes of peroxidation, the products of which inhibit the vasodilating function of the endothelium. In arterial hypertension, increased mechanical pressure on the walls of blood vessels leads to a disruption in the architectonics of endothelial cells, an increase in their permeability to albumin, an increase in the secretion of vasoconstrictive endothelin-1, and remodeling of the walls of blood vessels. Dyslipidemia increases the expression of adhesive molecules on the surface of endothelial cells, which gives rise to the formation of atheroma. Thus, all of the above conditions, by increasing the permeability of the endothelium, the expression of adhesive molecules, reducing the endothelium-dependent relaxation of blood vessels, contribute to the progression of atherogenesis.

Proponents of another hypothesis believe that endothelial dysfunction is not a consequence, but the cause of the development of IR and related conditions (hyperglycemia, hypertension, dyslipidemia). Indeed, in order to bind to its receptors, insulin must cross the endothelium and enter the intercellular space. In the case of a primary defect in endothelial cells, transendothelial transport of insulin is impaired. Therefore, an IR condition may develop. In this case, IR will be secondary to endotheliopathy (Fig. 1).

Rice. 1. Possible role of endothelial dysfunction in the development of insulin resistance syndrome

In order to prove this point of view, it is necessary to examine the state of the endothelium before the onset of symptoms of IR, i.e. in individuals at high risk of developing metabolic syndrome. Presumably, children born with low birth weight (less than 2.5 kg) are at high risk of developing IR syndrome. It is in these children that later in adulthood all the signs of the metabolic syndrome appear. This is attributed to insufficient intrauterine capillarization of developing tissues and organs, including the pancreas, kidneys, and skeletal muscles. When examining children aged 9-11 years old who were born with low birth weight, a significant decrease in endothelium-dependent vascular relaxation and a low level of anti-atherogenic high-density lipoprotein fraction were found, despite the absence of other signs of IR. This study suggests that, indeed, endotheliopathy is primary in relation to IR.

To date, there has not been sufficient data in favor of the primary or secondary role of endotheliopathy in the genesis of IR. At the same time, it is undeniable that that endothelial dysfunction is the first link in the development of atherosclerosis associated with IR syndrome . Therefore, the search for therapeutic options for restoring impaired endothelial function remains the most promising in the prevention and treatment of atherosclerosis. All conditions included in the concept of metabolic syndrome (hyperglycemia, arterial hypertension, hypercholesterolemia) aggravate endothelial cell dysfunction. Therefore, the elimination (or correction) of these factors will certainly improve the function of the endothelium. Antioxidants that eliminate the damaging effects of oxidative stress on vascular cells, as well as drugs that increase the production of endogenous nitric oxide (NO), such as L-arginine, remain promising drugs that improve endothelial function.

Table 2 lists drugs that have been shown to be anti-atherogenic by improving endothelial function. These include: statins ( simvastatin ), angiotensin-converting enzyme inhibitors (in particular, enalapril ), antioxidants, L-arginine, estrogens.

Experimental and clinical studies to identify the primary link in the development of IR are ongoing. At the same time, there is a search for drugs that can normalize and balance the functions of the endothelium in various manifestations of the insulin resistance syndrome. At present, it has become quite obvious that this or that drug can only have an antiatherogenic effect and prevent the development of cardiovascular diseases if it directly or indirectly restores the normal function of endothelial cells.

Simvastatin -

Zokor (trade name)

(Merck Sharp & Dohme Idea)

Enalapril -

Vero-enalapril (trade name)

(Veropharm CJSC)

Tatyana Khmara, cardiologist, I.V. Davydovsky about a non-invasive method for diagnosing atherosclerosis at an early stage and the selection of an individual program of aerobic exercise for the recovery period of patients with myocardial infarction.

To date, the FMD test (assessment of endothelial function) is the "gold standard" for non-invasive assessment of the state of the endothelium.

ENDOTHELIAL DYSFUNCTION

The endothelium is a single layer of cells lining the inner surface of blood vessels. Endothelial cells perform many of the functions of the vascular system, including vasoconstriction and vasodilation, to control blood pressure.

All cardiovascular risk factors (hypercholesterolemia, arterial hypertension, impaired glucose tolerance, smoking, age, overweight, sedentary lifestyle, chronic inflammation, and others) lead to dysfunction of endothelial cells.

Endothelial dysfunction is an important precursor and early marker of atherosclerosis, it makes it possible to fairly informatively evaluate the choice of treatment for arterial hypertension (if the choice of treatment is adequate, then the vessels respond correctly to therapy), and also often allows timely detection and correction of impotence in the early stages.

Assessment of the state of the endothelial system formed the basis of the FMD test, which allows you to identify risk factors for the development of cardiovascular diseases.

HOW IT IS CARRIED OUTFMD TEST:

The non-invasive FMD method involves a vessel stress test (similar to a stress test). The sequence of the test consists of the following steps: measuring the initial diameter of the artery, clamping the brachial artery for 5-7 minutes and re-measuring the diameter of the artery after removing the clamp.

During compression, the volume of blood in the vessel increases and the endothelium begins to produce nitric oxide (NO). During the release of the clamp, blood flow is restored and the vessel expands due to the accumulated nitric oxide and a sharp increase in blood flow velocity (by 300–800% of the initial one). After a few minutes, the expansion of the vessel reaches its peak. Thus, the main parameter monitored by this technique is the increase in the diameter of the brachial artery (%FMD is usually 5-15%).

Clinical statistics show that in people with an increased risk of developing cardiovascular diseases, the degree of vasodilation (% FMD) is lower than in healthy people due to the fact that endothelial function and nitric oxide (NO) production are impaired.

WHEN TO CARRY OUT A STRESS TEST OF VESSELS

Evaluation of endothelial function is the starting point to understand what is happening with the vascular system of the body even at the initial diagnosis (for example, a patient presents with vague chest pain). Now it is customary to look at the initial state of the endothelial bed (whether there is a spasm or not) - this allows you to understand what is happening with the body, whether there is arterial hypertension, whether there is vasoconstriction, whether there are any pains associated with coronary heart disease.

Endothelial dysfunction is reversible. With the correction of risk factors that led to disorders, the function of the endothelium is normalized, which makes it possible to monitor the effectiveness of the therapy used and, with regular measurement of endothelial function, to select an individual program of aerobic exercise.

SELECTION OF AN INDIVIDUAL PROGRAM OF AEROBIC PHYSICAL ACTIVITY

Not every load has a good effect on the vessels. Too intense exercise can lead to endothelial dysfunction. It is especially important to understand the limits of the load for patients in the recovery period after heart surgery.

For such patients in the City Clinical Hospital. I.V. Davydovsky, under the guidance of the Head of the University Clinic of Cardiology, Professor A.V. Shpektr, developed a special method for selecting an individual program of physical activity. In order to select the optimal physical activity for the patient, we measure the %FMD readings at rest, with minimal physical exertion and at the limit of the load. Thus, both the lower and upper limits of the load are determined, and an individual load program is selected for the patient, the most physiological for each person.

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 a healthy endothelium and its normal function causes expansion 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, like a unicellular inner layer, covers the walls of blood vessels from the inside, makes it vulnerable to various influences and known cardiovascular risk factors. 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 have 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 has been 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).

Non-drug treatments for endothelial dysfunction include diet therapy aimed at lowering serum cholesterol levels, systematic exercise, and avoidance of cigarette and alcohol consumption. 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 grounds for the use of calcium channel blockers and estrogen replacement therapy in relation to 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. From the point of view of the impact on the cause of endothelial dysfunction, 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 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 gonadotropin 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 coronary artery disease (4S studies, 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. 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 (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 perhaps even improve the prognosis in such patients.

Functional restructuring of the endothelium under the influence of pathological factors goes through several stages:

I stage - increased synthetic activity of endothelial cells, the endothelium works as a “biosynthetic machine”.

III stage - depletion of the endothelium, accompanied by cell death and slow processes of endothelial regeneration.

Rice. 1. Possible role of endothelial dysfunction in the development of insulin resistance syndrome

Simvastatin -

Zokor (trade name)

(Merck Sharp & Dohme Idea)

Enalapril -

Vero-enalapril (trade name)

(Veropharm CJSC)

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

The endothelium is a single-layer layer of specialized cells of mesenchymal origin, lining the blood, lymphatic vessels and cavities of the heart.

Endothelial cells that line blood vessels have amazing ability change their number and location in accordance with local requirements. Almost all tissues need a blood supply, and this in turn depends on endothelial cells. These cells create a flexible, adaptable life support system with branches throughout the body. Without this ability of endothelial cells to expand and repair the blood vessel network, 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 transfer of substances from tissues to the blood and back. Moreover, embryonic studies have shown that the arteries and veins themselves develop from simple small vessels made entirely of endothelial cells and basement membranes: connective tissue and smooth muscle where needed are added later by signals from endothelial cells.

In the familiar form of human consciousness 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 . In morphological terms, the endothelium resembles a single-layer squamous epithelium and, in a calm state, appears as a layer consisting of individual cells. In their form, endothelial cells look like very thin plates of irregular shape and various lengths. Along with elongated, spindle-shaped cells, one can often see cells with rounded ends. An oval-shaped nucleus is located in the central part of the endothelial cell. Usually, most cells have one nucleus. In addition, there are cells that do not have a nucleus. It decomposes in the protoplasm in the same way as it takes place in erythrocytes. These non-nuclear cells undoubtedly represent dying cells that have completed their life cycle. In the protoplasm of endothelial cells, one can see all the typical inclusions (the Golgi apparatus, chondriosomes, small grains of lipoids, sometimes grains of pigment, etc.). At the moment of contraction, very often the thinnest fibrils appear in the protoplasm of cells, which are formed in the exoplasmic layer and are very reminiscent of 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; under various stimuli, the cells sharply change their character and take on the appearance of cells that are almost completely indistinguishable from fibroblasts. In its 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, which forms integumentary plates. Many studies assume that a special cementing substance is secreted between endothelial cells, which glues the cells together. In recent years, interesting data have been obtained that allow us to assume that the light 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. Studying the fate and transformation of the excited endothelium, it can be concluded that endothelial cells in different vessels are at different stages of differentiation. Thus, the endothelium of the sinus capillaries of the hematopoietic organs is directly connected with the reticular tissue surrounding it and, in its ability to further transformations, does not differ markedly from the cells of this latter - in other words, the described endothelium is poorly differentiated and has some potencies. The endothelium of large vessels, in all likelihood, already consists of more highly specialized cells that have lost the ability to undergo any transformations, and therefore it can be compared with connective tissue fibrocytes.

The endothelium is not a passive barrier between blood and tissues, but an active organ, the 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, 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 of the surface of the endothelium and platelets prevents "adhesion" - adhesion - of platelets to the vessel wall; coagulation also prevents the formation of prostacyclin, NO (natural antiplatelet agents) and the formation of t-PA (tissue plasminogen activator); no less important is 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 (stimulator of T-lymphocytes)
enzymatic activity- expression on the surface of endothelial cells of angiotensin-converting enzyme - ACE (conversion of AI to AII)
involved in the regulation of smooth muscle cell growth via 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 its functional state, which is largely determined by the incoming information that it perceives. The endothelium has 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.

The secretory activity of the endothelium stimulates:
change in blood flow velocity such as increased blood pressure
secretion of neurohormones- catecholamines, vasopressin, acetylcholine, bradykinin, adenosine, histamine, etc.
factors released from platelets when they are activated- serotonin, ADP, thrombin

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

endothelial dysfunction, which occurs under the influence of damaging agents (mechanical, infectious, metabolic, immune complex, etc.), sharply changes the direction of its endocrine activity to the opposite: vasoconstrictors, 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 updated, obsolete fragments, together with biologically active substances, enter the bloodstream, 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 endotheliocytes can be divided into the following groups:
factors that regulate vascular smooth muscle tone:
- constrictors- endothelin, angiotensin II, thromboxane A2
- dilators- nitric oxide, prostacyclin, endothelial depolarization factor
hemostasis factors:
- antithrombogenic- nitric oxide, tissue plasminogen activator, prostacyclin
- prothrombogenic- platelet 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 affecting inflammation- tumor necrosis factor, superoxide radicals

Normally, in response to stimulation, the endothelium reacts by increasing the synthesis of substances that cause relaxation of the 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 of 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 mandatory participants in all phases of hemostasis and muscle contraction. cGMP, by activating cGMP-dependent proteinase, creates conditions for the opening of numerous potassium and calcium channels. Proteins play a particularly important role - 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, whose density on membranes is very high, is the main mechanism of action of nitric oxide. Therefore, the net effect of NO is antiaggregatory, 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 the vessels. Nitric oxide acts as a neurotransmitter, a translator of nerve impulses, participates 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 action of acetylcholine, kinins, serotonin, catecholamines, etc. In intact endothelium, many vasodilators (histamine, bradykinin, acetylcholine, etc.) have a vasodilating effect through nitric oxide. Especially strongly NO dilates cerebral vessels. If the functions of the endothelium are impaired, acetylcholine causes either a weakened or perverted reaction. Therefore, the reaction of vessels 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 the level of nitric oxide takes place under the influence of glucocorticoids, which inhibit 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 ratio between nitric oxide (antiplatelet agent, anticoagulant, vasodilator) and peroxynitrate, which increases the level of oxidative stress, which leads to serious consequences.

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

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

As long as the endothelium is intact, not damaged, it synthesizes mainly anticoagulant factors, which are also vasodilators. These biologically active substances prevent the growth of smooth muscles - the walls of the vessel do not thicken, its diameter does not change. In addition, the endothelium adsorbs numerous anticoagulants from the 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 the exposure of the subendothelial layers triggers aggregation and coagulation reactions that prevent blood loss, causes a spasm of the vessel, which can be very strong and is not eliminated by denervation of the vessel. Stops the formation of antiplatelet agents. With a short-term action of 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, aggregants 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, are faced with patients in whom the consequences of endothelial dysfunction have already become symptoms of cardiovascular disease. Rational therapy should be aimed at eliminating these symptoms (clinical manifestations of endothelial dysfunction may be vasospasm and thrombosis). Treatment of endothelial dysfunction is aimed at restoring the dilatory vascular response.

Drugs with the potential to affect endothelial function can be divided into four main categories:
replacing natural projective endothelial substances- stable analogues of PGI2, 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, a lazaroid inhibitor of free radical production
lipid-lowering drugs

Recently installed the important role of magnesium in the development of endothelial dysfunction. It was 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 relationship between the degree of endothelium-dependent vasodilation and the concentration of intracellular magnesium. One of the possible mechanisms explaining the beneficial effect of magnesium on endothelial function may be its antiatherogenic potential.