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

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

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

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

In a form familiar to human consciousness The endothelium is an organ weighing 1.5-1.8 kg (comparable to the weight of, for example, the liver) or a continuous monolayer of endothelial cells 7 km long, or occupying the area of ​​a football field or six tennis courts. Without these spatial analogies, it would be difficult to imagine that a thin semi-permeable membrane separating the blood flow from the deep structures of the vessel continuously produces a huge amount of the most important biologically active substances, thus being a giant paracrine organ distributed throughout the entire territory of the human body.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Catad_tema Arterial hypertension - articles

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

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

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

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

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

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

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

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

The role of the endothelium in cardiovascular pathology

In the form familiar to human consciousness, the endothelium is an organ weighing 1.5-1.8 kg (comparable to the weight of, for example, the liver) or a continuous monolayer of endothelial cells 7 km long, or occupying the area of ​​a football field, or six tennis courts. Without these spatial analogies, it would be difficult to imagine that a thin semi-permeable membrane separating the blood flow from the deep structures of the vessel continuously produces a huge amount of the most important biologically active substances, thus being a giant paracrine organ distributed throughout the entire territory of the human body.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Scheme 1. MECHANISMS OF ENDOTHELIAL DYSFUNCTION
FOR CARDIOVASCULAR DISEASES

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

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

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

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

Endothelial function assessment

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

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

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

Therapeutic Strategies

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

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

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

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

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

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

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

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

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

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

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The endothelium is a layer of flattened cells of mesenchymal origin, lining the walls of blood and lymphatic vessels and capillaries, ensuring exchange processes between blood and tissues. It is a continuous membrane consisting of a layer of endothelial cells connected by intercellular “cement”. The endothelium of the blood capillaries of some organs is interrupted due to the presence of submicroscopic intracellular “pores” (in the kidneys, endocrine glands, intestines) or wide intercellular gaps (in the liver, spleen, bone marrow).

Planar preparation of the inner lining of a muscular artery: 1 - endothelial cells; 2 - cells of the subendothelial layer; 3 - boundaries between endothelial cells (according to Shchelkunov).

Endothelium [from Greek. endon - inside + (epi)thelium] - a layer of flattened cells of mesenchymal origin lining the walls of blood and lymphatic vessels. In embryogenesis, the endothelium first appears as a result of special differentiation of mesenchymal cells, forming a closed single-layer layer of cells in the form of blood islands, located in the wall of the yolk sac and chorion at the 2-3rd week of intrauterine development. Most authors consider the endothelium to be a product of highly differentiated mesenchymal cells. Some authors classify the endothelium as a unique, highly specific type of epithelial tissue (angiodermal). Endothelial cells are thin plates, closely adjacent to each other and forming a continuous single-layer layer (Fig.). The length of endothelial cells is from 5 μm to 175 μm, the thickness in the perinuclear areas is from 200 Å to 1-2 μm. The tortuous cell boundaries are well impregnated with silver nitrate. The polygonal shape of the cells is varied and depends on the size of the vessel and the degree of its stretching. The nuclei of endothelial cells are oval in shape, with a long diameter, located along the length of the vessel.

Endothelial cells often contain one nucleus, sometimes 2-3; there are symplasts with 10 or more nuclei. In endothelial cells, pinocytotic vesicles with a diameter of 500-1000 Å were found, located near the outer and inner surfaces. On the surface of the endothelium, facing the blood flow, there are submicroscopic villi. In the cytoplasm of the endothelium, an endoplasmic reticulum with numerous RNA granules on its membranes and small mitochondria were detected. Intercellular spaces 100 Å wide do not contain intercellular cement. A scaly overlap of two adjacent endothelial cells is observed. Micropores with a diameter of 300-400 Å were found in the endothelium of the capillaries of the kidney glomeruli, intestinal villi, and endocrine glands. The endothelium of blood capillaries is surrounded by a basement membrane, which is absent in the endothelium of lymphatic capillaries. Glycogen, vitamin C, and alkaline phosphatase were detected in the endothelium. The endothelium of the endocardium and large vessels is the most differentiated, the endothelium of the capillaries is less differentiated. Endothelial cells divide by mitosis and amitosis. During reparative regeneration, restoration of the endothelium occurs through mitotic division of its cells at the edge of the wound and their creep onto the damaged surface. Endothelial restoration also occurs from poorly differentiated mesenchymal elements located in the subendothelial layer. New formation of capillaries occurs due to the fusion of kidney-shaped outgrowths of the endothelium with each other. The endothelium lining the sinusoidal capillaries of the liver, bone marrow, spleen and sinuses of the lymph nodes has a pronounced ability to accumulate foreign colloids from the blood and lymph. This endothelium belongs to the elements of the reticuloendothelial system (see). Through the endothelium, metabolism occurs between blood (or lymph) and tissue fluid.

We noted earlier that the composition of the blood is significantly influenced by the endothelium of the vascular wall. It is known that the diameter of the average capillary is 6-10 microns, its length is about 750 microns. The total cross-section of the vascular bed is 700 times the diameter of the aorta. The total area of ​​the capillary network is 1000 m2. If we take into account that pre- and post-capillary vessels participate in the exchange, this value doubles. Dozens, and most likely hundreds, of biochemical processes associated with intercellular metabolism take place here: its organization, regulation, and implementation. According to modern concepts, the endothelium is an active endocrine organ, the largest in the body and diffusely scattered throughout all tissues. The endothelium synthesizes compounds important for blood clotting and fibrinolysis, platelet adhesion and aggregation. It regulates the activity of the heart, vascular tone, blood pressure, filtration function of the kidneys and metabolic activity of the brain. It controls the diffusion of water, ions, and metabolic products. The endothelium responds to mechanical blood pressure (hydrostatic pressure). Considering the endocrine functions of the endothelium, British pharmacologist and Nobel Prize winner John Vane called the endothelium “the maestro of blood circulation.”

The endothelium synthesizes and secretes a large number of biologically active compounds, which are released according to current needs. The functions of the endothelium are determined by the presence of the following factors:

1. controlling the contraction and relaxation of the muscles of the vascular wall, which determines its tone;

2. participating in the regulation of the fluid state of the blood and promoting thrombus formation;

3. controlling the growth of vascular cells, their repair and replacement;

4. taking part in the immune response;

5. Participating in the synthesis of cytomedins or cellular mediators that ensure the normal functioning of the vascular wall.

Nitric oxide. One of the most important molecules produced by the endothelium is nitric oxide, the final substance that carries out many regulatory functions. Nitric oxide is synthesized from L-arginine by the constitutive enzyme NO synthase. To date, three isoforms of NO synthases have been identified, each of which is the product of a separate gene, encoded and identified in different cell types. In endothelial cells and cardiomyocytes there is a so-called NO synthase 3 (ecNOs or NOs3)

Nitric oxide is present in all types of endothelium. Even at rest, the endothelial cell synthesizes a certain amount of NO, maintaining basal vascular tone.

With contraction of the muscular elements of the vessel, a decrease in the partial oxygen tension in the tissue in response to an increase in the concentration of acetylcholine, histamine, norepinephrine, bradykinin, ATP, etc., the synthesis and secretion of NO by the endothelium increases. The production of nitric oxide in the endothelium also depends on the concentration of calmodulin and Ca 2+ ions.

The function of NO is reduced to inhibiting the contractile apparatus of smooth muscle elements. In this case, the enzyme guanylate cyclase is activated and an intermediary (messenger) is formed - cyclic 3 / 5 / -guanosine monophosphate.

It has been established that incubation of endothelial cells in the presence of one of the proinflammatory cytokines, TNFa, leads to a decrease in the viability of endothelial cells. But if the formation of nitric oxide increases, then this reaction protects endothelial cells from the action of TNFa. At the same time, the adenylate cyclase inhibitor 2/5/-dideoxyadenosine completely suppresses the cytoprotective effect of the NO donor. Therefore, one of the ways NO may act is through cGMP-dependent inhibition of cAMP breakdown.

What does NO do?

Nitric oxide inhibits the adhesion and aggregation of platelets and leukocytes, which is associated with the formation of prostacyclin. At the same time, it inhibits the synthesis of thromboxane A 2 (TxA 2). Nitric oxide inhibits the activity of angiotensin II, which causes an increase in vascular tone.

NO regulates local endothelial cell growth. Being a free radical compound with high reactivity, NO stimulates the toxic effect of macrophages on tumor cells, bacteria and fungi. Nitric oxide counteracts oxidative damage to cells, likely due to the regulation of intracellular glutathione synthesis mechanisms.

The weakening of NO generation is associated with the occurrence of hypertension, hypercholesterolemia, atherosclerosis, as well as spastic reactions of the coronary vessels. In addition, disruption of the generation of nitric oxide leads to endothelial dysfunction regarding the formation of biologically active compounds.

Endothelin. One of the most active peptides secreted by the endothelium is the vasoconstrictor factor endothelin, the effect of which is manifested in extremely small doses (one millionth of a mg). There are 3 isoforms of endothelin in the body, which differ extremely little from each other in their chemical composition, each containing 21 amino acid residues and differ significantly in their mechanism of action. Each endothelin is the product of a separate gene.

Endothelin 1 – the only one of this family that is formed not only in the endothelium, but also in smooth muscle cells, as well as in neurons and astrocytes of the brain and spinal cord, mesangial cells of the kidney, endometrium, hepatocytes and epithelial cells of the mammary gland. The main stimuli for the formation of endothelin 1 are hypoxia, ischemia and acute stress. Up to 75% of endothelin 1 is secreted by endothelial cells towards the smooth muscle cells of the vascular wall. In this case, endothelin binds to receptors on their membrane, which ultimately leads to their constriction.

Endothelin 2 – The main places of its formation are the kidneys and intestines. It is found in small quantities in the uterus, placenta and myocardium. Its properties are practically no different from endothelin 1.

Endothelin 3 constantly circulates in the blood, but its source of formation is unknown. It is found in high concentrations in the brain, where it is thought to regulate functions such as the proliferation and differentiation of neurons and astrocytes. Additionally, it is found in the gastrointestinal tract, lungs and kidneys.

Considering the functions of endothelins, as well as their regulatory role in intercellular interactions, many authors believe that these peptide molecules should be classified as cytokines.

Endothelin synthesis is stimulated by thrombin, epinephrine, angiotensin, interleukin-I (IL-1) and various growth factors. In most cases, endothelin is secreted from the endothelium inward, to muscle cells, where receptors sensitive to it are located. There are three types of endothelin receptors: A, B and C. All of them are located on the membranes of cells of various organs and tissues. Endothelial receptors are classified as glycoproteins. Most of the endothelin synthesized interacts with EtA receptors, a smaller part - with EtB-type receptors. The action of endothelin 3 is mediated through ETS receptors. At the same time, they are able to stimulate the synthesis of nitric oxide. Consequently, with the help of the same factor, two opposite vascular reactions are regulated - contraction and relaxation, realized by different mechanisms. It should be noted, however, that under natural conditions, when there is a slow accumulation of endothelin concentrations, a vasoconstrictor effect is observed due to the contraction of vascular smooth muscle.

Endothelin is certainly involved in coronary heart disease, acute myocardial infarction, cardiac arrhythmias, atherosclerotic vascular damage, pulmonary and cardiac hypertension, ischemic brain damage, diabetes and other pathological processes.

Thrombogenic and thromboresistant properties of the endothelium. The endothelium plays an extremely important role in maintaining the fluid state of the blood. Damage to the endothelium inevitably leads to adhesion (sticking) of platelets and leukocytes, resulting in the formation of white (consisting of platelets and leukocytes) or red (including red blood cells) blood clots. In connection with the above, we can assume that the endocrine function of the endothelium is reduced, on the one hand, to maintaining the liquid state of the blood, and on the other, to the synthesis and release of factors that can lead to stopping bleeding.

Factors that help stop bleeding include a complex of compounds leading to platelet adhesion and aggregation, formation and preservation of a fibrin clot. Compounds that ensure the liquid state of blood include inhibitors of platelet aggregation and adhesion, natural anticoagulants and factors leading to the dissolution of the fibrin clot. Let us dwell on the characteristics of the listed compounds.

It is known that substances that induce platelet adhesion and aggregation and are produced by the endothelium include thromboxane A 2 (TxA 2), von Willebrand factor (vWF), platelet activating factor (PAF), and adenosine diphosphoric acid (ADP).

TxA 2, is mainly synthesized in the platelets themselves, but this compound can also be formed from arachidonic acid, which is part of endothelial cells. The action of TxA 2 occurs in the event of endothelial damage, resulting in irreversible platelet aggregation. It should be noted that TxA 2 has a fairly strong vasoconstrictor effect and plays an important role in the occurrence of coronary spasm.

vWF is synthesized by intact endothelium and is required for both platelet adhesion and aggregation. Different vessels are able to synthesize this factor to varying degrees. A high level of vWF transport RNA was found in the vascular endothelium of the lungs, heart, and skeletal muscles, while in the liver and kidneys its concentration is relatively low.

PAF is produced by many cells, including endothelial cells. This compound promotes the expression of the main integrins involved in the processes of platelet adhesion and aggregation. PAF has a wide spectrum of action and plays an important role in the regulation of physiological functions of the body, as well as in the pathogenesis of many pathological conditions.

One of the compounds involved in platelet aggregation is ADP. When the endothelium is damaged, mainly adenosine triphosphate (ATP) is released, which, under the action of cellular ATPase, quickly turns into ADP. The latter triggers the process of platelet aggregation, which in the first stages is reversible.

The action of compounds that promote platelet adhesion and aggregation is counteracted by factors that inhibit these processes. These primarily include prostacyclin or prostaglandin I 2 (PgI 2). The synthesis of prostacyclin by intact endothelium occurs constantly, but its release is observed only in the event of the action of stimulating agents. PgI 2 inhibits platelet aggregation due to the formation of cAMP. In addition, inhibitors of platelet adhesion and aggregation are nitric oxide (see above) and ecto-ADPase, which breaks down ADP to adenosine, which serves as an aggregation inhibitor.

Factors that promote blood clotting. This should include tissue factor, which under the influence of various agonists (IL-1, IL-6, TNFa, adrenaline, lipopolysaccharide (LPS) of gram-negative bacteria, hypoxia, blood loss) is intensively synthesized by endothelial cells and enters the bloodstream. Tissue factor (FIII) triggers the so-called extrinsic clotting pathway. Under normal conditions, tissue factor is not produced by endothelial cells. However, any stressful situations, muscle activity, the development of inflammatory and infectious diseases lead to its formation and stimulation of the blood clotting process.

TO factors that prevent blood clotting, include natural anticoagulants. It should be noted that the surface of the endothelium is covered with a complex of glycosaminoglycans that have anticoagulant activity. These include heparan sulfate, dermatan sulfate, which can bind to antithrombin III, as well as increase the activity of heparin cofactor II and thereby increase the antithrombogenic potential.

Endothelial cells synthesize and secrete 2 extrinsic coagulation pathway inhibitors (TFPI-1 And TFPI-2), blocking the formation of prothrombinase. TFPI-1 is able to bind factors VIIa and Xa on the surface of tissue factor. TFPI-2, being an inhibitor of serine proteases, neutralizes coagulation factors involved in the extrinsic and intrinsic pathways of prothrombinase formation. At the same time, it is a weaker anticoagulant than TFPI-1.

Endothelial cells synthesize antithrombin III (A-III), which, when interacting with heparin, neutralizes thrombin, factors Xa, IXa, kallikrein, etc.

Finally, natural anticoagulants synthesized by the endothelium include thrombomodulin–protein C (PtC) system, which also includes protein S (PtS). This complex of natural anticoagulants neutralizes factors Va and VIIIa.

Factors influencing fibrinolytic activity of blood. The endothelium contains a complex of compounds that promote and prevent the dissolution of the fibrin clot. First of all, you should point out tissue plasminogen activator (TPA)– the main factor that converts plasminogen into plasmin. In addition, the endothelium synthesizes and secretes urokinase plasminogen activator. It is known that the latter compound is also synthesized in the kidneys and is excreted in the urine.

At the same time, the endothelium synthesizes and tissue plasminogen activator inhibitors (ITPA) types I, II and III. They all differ in their molecular weight and biological activity. The most studied of them is ITAP type I. It is constantly synthesized and secreted by endothelial cells. Other ITAPs play a less prominent role in the regulation of fibrinolytic activity of the blood.

It should be noted that under physiological conditions the effect of fibrinolysis activators prevails over the effect of inhibitors. Under stress, hypoxia, and physical activity, along with acceleration of blood clotting, activation of fibrinolysis is observed, which is associated with the release of tPA from endothelial cells. Meanwhile, tPA inhibitors are found in excess in endothelial cells. Their concentration and activity prevail over the effect of tPA, although entry into the bloodstream under natural conditions is significantly limited. When tPA reserves are depleted, which is observed during the development of inflammatory, infectious and oncological diseases, in pathologies of the cardiovascular system, in normal and especially pathological pregnancy, as well as in genetically determined insufficiency, the effect of ITAP begins to predominate, due to which, along with the acceleration of blood clotting inhibition of fibrinolysis develops.

Factors regulating the growth and development of the vascular wall. It is known that the endothelium synthesizes vascular growth factor. At the same time, the endothelium contains a compound that inhibits angiogenesis.

One of the main factors of angiogenesis is the so-called vascular endothelial growth factor or VGEF(from the words vascular growth endothelial cell factor), which has the ability to induce chemotaxis and mitogenesis of ECs and monocytes and plays an important role not only in neoangiogenesis, but also in vasculogenesis (early formation of blood vessels in the fetus). Under its influence, the development of collaterals is enhanced and the integrity of the endothelial layer is maintained.

Fibroblast growth factor (FGF) is related not only to the development and growth of fibroblasts, but is also involved in the control of the tone of smooth muscle elements.

One of the main inhibitors of angiogenesis, affecting the adhesion, growth and development of endothelial cells, is thrombospondin. It is a glycoprotein of the cellular matrix, synthesized by various types of cells, including endothelial cells. Thrombospondin synthesis is controlled by the P53 oncogene.

Factors involved in immunity. It is known that endothelial cells play an extremely important role in the implementation of both cellular and humoral immunity. It has been established that endothelial cells are antigen-presenting cells (APC), that is, they are capable of processing antigen (Ag) into an immunogenic form and “presenting” it to T- and B-lymphocytes. The surface of endothelial cells contains HLA of both classes I and II, which serves as a necessary condition for antigen presentation. A complex of polypeptides that enhance the expression of receptors on T- and B-lymphocytes has been isolated from the vascular wall and, in particular, from the endothelium. At the same time, endothelial cells are capable of producing a number of cytokines that contribute to the development of the inflammatory process. Such connections include IL-1 a and b, TNFa, IL-6, a- and b-chemokines and others. In addition, endothelial cells secrete growth factors that influence hematopoiesis. These include granulocyte colony-stimulating factor (G-CSF, G-CSF), macrophage colony-stimulating factor (M-CSF, M-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF, G-MCSF) and others. Recently, a compound of a polypeptide nature was isolated from the vascular wall, which sharply enhances the processes of erythropoiesis and contributes in the experiment to the elimination of hemolytic anemia caused by the introduction of carbon tetrachloride.

Cytomedins. Vascular endothelium, like other cells and tissues, is a source of cellular mediators – cytomedins. Under the influence of these compounds, which are a complex of polypeptides with a molecular weight from 300 to 10,000 D, the contractile activity of the smooth muscle elements of the vascular wall is normalized, due to which blood pressure is maintained within normal limits. Cytomedins from blood vessels promote the processes of tissue regeneration and repair and, possibly, ensure the growth of blood vessels when they are damaged.

Numerous studies have established that all biologically active compounds synthesized by the endothelium or arising in the process of partial proteolysis are, under certain conditions, capable of entering the vascular bed and thus influencing the composition and functions of the blood.

Of course, we have not presented a complete list of factors synthesized and secreted by the endothelium. However, this information is sufficient to conclude that the endothelium is a powerful endocrine network that provides regulation of numerous physiological functions.

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The wall of intact arteries consists of three membranes: intima (tunica intima), media (tunica media) and adventitia (tunica externa).

1. Intima, i.e. the inner shell includes the endothelium, a thin subendothelial layer and an internal elastic membrane at the border with the media - the middle shell. The endothelium is a monolayer of elongated cells oriented along the longitudinal axis of the vessel. The endothelial layer is fragile, its integrity is easily damaged by various physical influences, and restoration occurs due to the mitotic division of endothelial cells under the influence of certain stimuli from the surrounding connective tissue and endothelial cells.

2. The media is represented by circular bundles of smooth muscle cells, which are separated from the outer layer by an elastic membrane consisting of longitudinally oriented thick elastic fibers and spirally arranged bundles of collagen fibrils.

3. Adventitia - the outer shell of the vascular wall consists of loose connective tissue containing a large number of fibroblasts and merges with the surroundings of the vessel. An important feature of adventypia is the presence of nerve endings and vasa vasorum - vessels that supply the arterial wall. Elastic fibers create resistive resistance, which increases with increasing blood pressure and thereby counteracts the dilation of the vessel.

Elastic resistance determines the basal component of vascular tone - this is a phylogenetically ancient mechanism of autoregulation of vascular tone, ensuring the preservation of the structural integrity of blood vessels under conditions of their stretching by blood pressure. Smooth muscle fibers, under the influence of neurohumoral factors, create active tension in the vascular wall (vasomotor component of vascular tone) and, accordingly, a certain amount of vessel lumen (volume of blood flow) in the “interests” of the body. The relationship between the basal and vasomotor components of vascular tone is different in different organs and tissues.

Smooth muscle and endothelial cells are of greatest importance for the functioning of blood vessels. Particular attention in modern medicine is drawn to the endothelium, which, as it turns out, is capable of synthesizing a very large range of biologically active substances at the border “blood - cells of tissues/organs” and thus performing the function of a “customs officer” at this border.

Endothelium – endocrine organ of the cardiovascular system

The totality of all endothelial cells (specialized cells of mesenchymal origin) forms the endothelial lining - a single-layer layer of cells that lines the entire “cardiovascular tree” from the inside: blood vessels, heart cavities, and lymphatic vessels. In an adult, the endothelial lining has a mass of 1.5-1.8 kg, consists of approximately one trillion cells that are capable of synthesizing biologically active molecules with different types of action - autocrine, paracrine and endocrine.

The structural organization of the endothelial lining varies in different vessels. For example, there are random and clustered types of organization of the endothelial monolayer. The first of them is characterized by a relatively random arrangement of endothelial cells, and in the second, endothelial cells of approximately the same size form clusters (cluster group). The heterogeneity of the endothelium is associated with the type of vessel (arteries, arterioles, capillaries, venules, veins), organ or tissue that they supply.

Endothelial cells are also heterogeneous in their structure, which depends mainly on cytoskeletal fibrils: active microfilaments, microtubules, intermediate filaments. These three types of fibrils, present in all cells, form different variants of the microarchitecture of the endothelial ion exchangers. Typical differences in cellular architecture are usually stable - they persist even when experimenters isolate cells from tissue and culture them in vitro.

However, in recent years it has been established that these differences are not irreversible: under the influence of certain signals acting on cells from the outside, or gene mutations, the architecture of endothelial cells can be radically rearranged, to the point that cells of one type can transform into cells of another type with a completely different cytoskeletal architecture. The process of transformation of the phenotype of cells, including endothelial cells, is currently included in the concept designated by the term “reprogramming”.

This process is attracting increasing attention in the aspect of modern understanding of the pathogenesis of various forms of pathology. The heterogeneity of endothelial cells is expressed not only in structural features, but also in their genetic and biosynthetic specificity. For example, endothelial cells of coronary, pulmonary and cerebral vessels, despite their histological similarity, differ very significantly in the types of expressed receptors and the range of biologically active molecules synthesized: enzymes, regulatory proteins, messenger proteins. Such heterogeneity determines the unequal participation of different populations of endothelial cells in the development of atherosclerosis, coronary heart disease, inflammation and other forms of pathology.

So, the endothelium is not only the main structural component of the intima, acting as a barrier between the blood and the basement membrane of the vascular wall, but also an active regulator of many vital processes. The variety of target effects of the “hormonal response” of endothelial cells is based on their ability to synthesize biologically active substances, which, for the most part, are functional antagonists. The set of these substances includes vasoconstrictors and vasodilators, proplatelet agents and antiplatelet agents, procoagulants and anticoagulants, mitogens and antimitogens.

The “hormonal” activity of intact endothelium promotes vasodilation, prevents hemocoagulation and thrombus formation, and limits the proliferative potential of vascular wall cells. In conditions of alteration (alteratio; lat. - change), i.e. pathogenetically significant changes in the endothelium, its “hormonal” response, on the contrary, promotes vasoconstriction, hemocoagulation, thrombus formation, and the proliferative process.

The endothelial lining is under constant “press” from extra- and intravascular factors, which, in fact, are regulators of the “hormonal response” of endothelial cells.

At the end of the last century, two types of response of endothelial cells to disturbing influences were identified: one of them develops immediately (without changing gene expression) and is expressed in the release of preformed and deposited biologically active molecules (for example: P-selectin, von Willebrand factor, platelet activating factor (PAF) from endothelial cell granules); the other - manifests itself 4-6 hours after the onset of the disturbing stimulus and is characterized by a change in the activity of genes that determine the de novo synthesis of adhesive molecules (for example: E-selecgan, ICAM-1, VCAM-1; interleukins IL-1 and IL-6; chemokines - IL-8, MCP-1 and other substances).

In general terms, we can distinguish 3 main groups of factors that induce a “hormonal response” of the endothelium.

1. Hemodynamic factor. The influence of this factor on the functional activity of the endothelium depends on the speed of blood flow, its nature, as well as the magnitude of blood pressure, which determine the development of the so-called. “shear stress”

2. “Cellular” (locally formed) biologically active substances with autocrine or paracrine properties. These include factors of the “release reaction” - degranulation and lysis of adhered and aggregated platelets: thromboplastin, fibrinogen, von Willebrand factor, platelet-derived growth factor, fibronectin, serotonin, ADP, acid hydrolases, as well as products of leukocytes that have moved to the edge, parietal position (formerly total neutrophils), which at the same time become intensive producers of adhesive molecules, lysosomal proteases, reactive oxygen species, leukotrienes, prostaglandins of group E, etc.), as well as activated mast cells - sources of histamine, serotonin, leukotrienes C4 and D4, activation factor platelets, heparin, proteolytic enzymes, chemotactic and other factors.

3. Circulating (distantly formed) biologically active substances with endocrine properties. These include catecholamines, vaeopressin, acetylcholine, bradykinin, adenosine, histamine and many others.

The action of mediators and neurohormones is mainly realized through specific receptors located on the surface of endothelial cells.

Damage to the endothelium, i.e. pathogenetically significant reprogramming of its biosynthetic activity during the development of various diseases is associated primarily with a significant change in “shear stress.” “Shear stress” (mechanical factor), by definition of this concept, is the internal forces that arise in a deformable body under the influence of external static and dynamic loads.

According to Hooke's law, the magnitude of elastic deformation of a solid is proportional to the applied mechanical stress. The elastic properties of the vascular wall are determined by the quantitative and qualitative characteristics of its structural components: connective tissue and smooth muscle cells organized into fibers.

The pressure in a blood vessel creates a “tensile (pressure-dependent) shear stress” in its wall, directed tangentially to the circumference of the vessel, and the speed of blood movement creates a “longitudinal (flow-dependent) shear stress,” oriented along the vessel. Thus, shear stress is the pressing and sliding mechanical forces acting on the surface of the endothelium.

In addition to these hemodynamic factors, the magnitude of shear stress is influenced by blood viscosity. It has been established that the arteries regulate their lumen according to changes in this property of the blood: with an increase in viscosity, the vessels increase their diameter, and with a decrease, they reduce it.

The severity and direction of the regulatory response of arteries to changes in the value of intravascular flow is not always unambiguous and depends on the initial tone of the arteries.

Regarding the mechanisms of implementation of changes in shear stress, first of all, the question arises about the ability of endothelial cells to perceive mechanical stimuli. This property of endothelial cells has been demonstrated in vivo and in vitro, while the issue of mechanosensors has not yet been finally resolved. However, it has been established that changes in shear stress can indirectly, through ion-selective channels, affect the membrane potential of endothelial cells and thereby - for the synthesis and release of NO.

It was also discovered that endothelial cells (including their nuclei) are able to orient themselves in the direction of blood flow, while changing the intensity of expression of biologically active substances depending on shear stress. It turned out that this orientation can be prevented by drugs that increase the content of intracellular cAMP.

It should be noted that many aspects of the rather complex biomechanics of the vascular wall, the relationship between blood pressure and flow are still at the stage of their study, but at the same time, at present, the position about the active role of the endothelium in the regulation and disorders of blood circulation has taken on the character of a paradigm.

Physiological (moderately expressed) shear stress always contributes to the implementation of the protective and adaptive capabilities of endothelial cells. Excessive shear stress does not always lead to the realization of the protective and adaptive potential of endothelial activity.

Most often, significant (in intensity or duration) changes in hemodynamic parameters, mainly blood flow and pressure, are accompanied by depletion or inadequate use of the functional capabilities of the endothelium, i.e., the development of endothelial dysfunction.