home→Gastritis→ What damages the endothelium. Endothelial dysfunction as a new concept for the prevention and treatment of cardiovascular diseases

What damages the endothelium. Endothelial dysfunction as a new concept for the prevention and treatment of cardiovascular diseases

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 on 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). 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” all other biologically active compounds. 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 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 these 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 persons with high risk development of the 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, 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) exacerbate 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 researches to identify the primary link in the development of IR continues. 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)

The endothelium is a layer of cells that covers all the blood and lymphatic vessels of the human body from the inside. The endothelium has many important functions, including:

Liquid Filtration
Maintenance of vascular tone
Hormone transport
Maintain normal blood clotting
Restoration of organs and tissues through the formation of new blood vessels
Regulation of the expansion and narrowing of the lumen of blood vessels.

Endothelial dysfunction is the disruption and loss of endothelial function. Unfortunately, with endothelial dysfunction, there is always a simultaneous violation of all its numerous functions, each of which is very important for the normal functioning of the body.

Moreover, endothelial dysfunction is the first (and reversible) stage of atherosclerosis, a process that leads to the formation of cholesterol plaques in blood vessels and is the leading cause of death worldwide.

What circumstances lead to endothelial dysfunction?

The most common and important factors in the development of endothelial dysfunction are:

Smoking
High fat diet
High blood pressure
Low physical activity
Elevated blood sugar

How does endothelial dysfunction manifest itself?

Manifestations of endothelial dysfunction are the formation of blood clots in the vessels, impaired blood supply to organs and tissues.

What role does endothelial dysfunction play in erectile dysfunction?

An erection of the penis is a phenomenon associated with the expansion of the lumen of the cavernous bodies of the penis and an increase in blood flow to them. Endothelial dysfunction leads to impaired production of vasodilators (nitric oxide - NO) and, thus, erectile dysfunction. Since the cavernous bodies are the site of accumulation of a large amount of endothelium, they become the most vulnerable to endothelial dysfunction. In men, erection problems are, most often, the first sign of problems with blood vessels. Therefore, men over 40 years of age and having complaints of worsening erection should definitely be examined by a cardiologist.

How can endothelial dysfunction be diagnosed?

Currently, there are absolutely safe and painless techniques based on the analysis of the amplitude and shape of the pulse wave, which allow you to accurately study the state of the endothelium in large and small vessels and make a conclusion about the presence or absence of endothelial dysfunction.

Who should be screened for endothelial dysfunction?

You smoke, regardless of your age and smoking experience
Suffering from being overweight
Have high blood pressure
You have been diagnosed with coronary heart disease, atherosclerosis, thrombosis
You have high blood sugar
Do you have any hormonal imbalances?
Do you have erection problems?
Are you concerned about the state of your blood vessels?

What should I do if I have endothelial dysfunction?

First of all, you need to get rid of bad habits, such as smoking, alcohol abuse, excess consumption of fats and simple sugars.

In addition, it is necessary to establish a number of useful habits, namely, increase the level of physical activity, eat regularly and properly, spend more time outdoors.

If lifestyle changes do not lead to an improvement in the condition of the endothelium, then the doctor may recommend a number of drugs that have a beneficial effect on the vascular endothelium.

Catad_theme 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.

At present, AH is considered as the most 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 AH to another in the same patient, but also the deliberate simplification of ideas about the 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 AH, which based AH on partial disturbances in the mechanisms of BP regulation, may partly be an argument against the use of a single antihypertensive agent for the treatment of AH. 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.

At present, serious attention in the views on hypertension has been given to metabolic factors, the number of which, however, increases with the accumulation of knowledge and the possibilities of laboratory diagnostics (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 1980s, showed a significant pathological contribution of disturbed 24-hour BP variability and features of circadian BP rhythms, in particular, a pronounced pre-morning rise, high circadian BP gradients and the absence of a nocturnal BP decrease, which largely associated with fluctuations in vascular tone.

Nevertheless, by the beginning of the new century, a direction clearly crystallized, which largely included the accumulated experience of fundamental research, on the one hand, and focused the attention of clinicians on a new object - the endothelium - as a target organ of AH, 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 the human mind, the endothelium is an organ weighing 1.5-1.8 kg (comparable to the weight, for example, of 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 opposite processes - a) vascular tone (vasodilation/vasoconstriction); b) anatomical structure vessels (synthesis/inhibition of proliferation factors); c) hemostasis (synthesis and inhibition of factors of fibrinolysis and platelet aggregation); 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 associated with 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 zone of maximum coronary artery stenosis, on the contrary, they often occur in places 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) 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 implementing CVD has become unifying.

Understanding the multifaceted role of the endothelium, already at a qualitatively new level, again leads to the well-known, but well-forgotten formula "human health is determined by the health of its blood vessels."

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

It is believed that drug or non-drug effects on 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 risk factors for endothelial dysfunction (DE) 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 vasodilatory, 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 of 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 thesis about the need to correct endothelial dysfunction (i.e., normalize endothelial function) as an indicator of the adequacy of antihypertensive therapy became the basis of one of the new clinical directions. The evolution of the tasks of antihypertensive therapy was concretized not only to the need to normalize the level of blood pressure, but also to normalize the function of the endothelium. In fact, this means that lowering blood pressure without correcting endothelial dysfunction (DE) 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 a violation of endothelium-dependent vasodilation - both in the coronary and peripheral circulation. And although the contribution of each of these factors to the development of atherosclerosis has not been fully determined, this does not 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 AH and CVD in general. Suffice it to say that the disturbed relationship between angiotensin II and NO is quite capable of determining the development of hypertension.

Normally functioning endothelium is characterized by continuous basal NO production by endothelial NO synthetase (eNOS) from L-arginine. This is necessary to maintain normal basal vascular tone. At the same time, NO has angioprotective properties, inhibiting the proliferation smooth muscle vessels and monocytes, and thereby preventing the pathological restructuring of the vascular wall (remodeling), 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 quite a few reasons for this. To summarize, 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 stores for endothelial NOS, accelerated NO metabolism (with increased formation of free radicals), or a combination of both.

Despite the versatility of NO effects, Dzau et Gibbons managed to schematically formulate the main clinical consequences chronic NO deficiency in the vascular endothelium, thus showing, on 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 the transendothelial migration of monocytes, maintains normal endothelial permeability for lipoproteins and monocytes, and inhibits LDL oxidation in the subendothelium. NO is able to inhibit the proliferation and migration of vascular smooth muscle cells, as well as their collagen synthesis. The administration of NOS inhibitors after vascular balloon angioplasty or under 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, activation and aggregation, activating tissue plasminogen activator. There is strong evidence to suggest 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 performing vasodilation in response to various stimuli - blood shear stress, acetylcholine, serotonin.

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

Assessment of endothelial function

The decrease in NO synthesis is the main factor in the development of DE. Therefore, it would seem that nothing is simpler than measuring NO as a marker of endothelial function. However, the instability and short lifetime of the molecule severely limit the application of this approach. The study of stable NO metabolites 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, the study of nitric oxide metabolites alone is unlikely to provide valuable information on 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. brachial artery using infusion of acetylcholine or serotonin, or using veno-occlusive plethysmography, as well as using the latest techniques - samples 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 can reflect the function of the endothelium: tissue plasminogen activator and its inhibitor, thrombomodulin, von Willebrand factor.

Therapeutic strategies

Evaluation of DE as a violation of endothelium-dependent vasodilation due to a decrease in NO synthesis, in turn, requires a revision of therapeutic strategies for influencing the endothelium in order to prevent or reduce damage to the vascular wall.

It has already been shown that improvement in endothelial function precedes the regression of structural atherosclerotic changes. Influencing bad habits - smoking cessation - leads to an improvement in endothelial function. Fatty food contributes to the deterioration of endothelial function in apparently healthy individuals. The intake of antioxidants (vitamin E, C) contributes to the correction of endothelial function and inhibits thickening of the intima. carotid artery. Physical exercise improve the condition of the endothelium even in heart failure.

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

At the same time, such a "specific" effect aimed at improving the synthesis of NO in patients with coronary artery disease or hypercholesterolemia, such as replacement therapy with L-arginine, the NOS substrate - synthetase, also leads to the correction of DE. Similar data were obtained with the use of 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, coronary artery disease. These data indicate real opportunity affect 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 that improve endothelial function indirectly through an indirect increase in NO synthesis and a decrease in NO degradation.

Positive effects on the endothelium have also been 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 the function of the endothelium.

In conclusion, we would like to emphasize that disturbances in vascular tone and cardiovascular remodeling lead to damage to target organs 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, 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 primarily associated with a deficiency in NO synthesis, the most important factor-regulator of vascular tone, but even more so. important factor, on which structural changes in the vascular wall depend.

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

Literature

1. Yu.V. Postnov. To the origins of primary hypertension: a bioenergy approach. Cardiology, 1998, N 12, S. 11-48.
2. Furchgott R.F., Zawadszki J.V. The obligatory role of endotnelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980:288:373-376.
3. Vane J.R., Anggard E.E., Batting R.M. Regulatory functions of the vascular endotnelium. New England Journal of Medicine, 1990: 323: 27-36.
4. Hahn A.W., Resink T.J., Scott-Burden T. et al. Stimulation of endothelin mRNA and secretion in rat vascular smooth muscle cells: a novel autocrine function. Cell regulation. 1990; 1:649-659.
5. Lusher T.F., Barton M. Biology of the endothelium. Clin. Cardiol, 1997; 10 (suppl 11), II - 3-II-10.
6. Vaughan D.E., Rouleau J-L., Ridker P.M. et al. Effects of ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction. Circulation, 1997; 96:442-447.
7 Cooke J.P, Tsao P.S. Is NO an endogenous antiatherogenic molecule? Arterioscler. Thromb. 1994; 14:653-655.
8. Davies M.J., Thomas A.S. Plaque fissuring - the cause of acute myocardial infarction, sudden ischemic death, and creshendo angina. Brit. Heart Journ., 1985: 53: 363-373.
9. Fuster V., Lewis A. Mechanisms leading to myocardial infarction: Insights from studies of vascular biology. Circulation, 1994:90:2126-2146.
10. Falk E., Shah PK, Faster V. Coronary plaque disruption. Circulation, 1995; 92:657-671.
11. Ambrose JA, Tannenhaum MA, Alexopoulos D et al. Angiographic progression of coronary artery disease ana the development of myocardial infarction. J.Amer. Coll. cardiol. 1988; 92:657-671.
12. Hacket D., Davies G., Maseri A. Pre-existing coronary stenosis in patients with first myocardial infarction are not necessary severe. Europ. Heart J. 1988, 9:1317-1323.
13. Little WC, Constantinescu M., Applegate RG et al. Can coronary angiography predict the site of subsequent myocardial infarction in patients with mils-to-moderatecoronary disease? Circulation 1988:78:1157-1166.
14. Giroud D., Li JM, Urban P, Meier B, Rutishauer W. Relation of the site of acute myocardial infarction to the most severe coronary arterial stenosis at prior angiography. amer. J. Cardiol. 1992; 69:729-732.
15 Furchgott RF, Vanhoutte PM. Endothelium-derived relaxing and contracting factors. FASEB J. 1989; 3: 2007-2018.
16. Vane JR. Anggard EE, Batting RM. Regulatory functions of the vascular endothelium. New Engl. J. Med. 1990; 323:27-36.
17. Vanhoutte PM, Mombouli JV. Vascular endothelium: vasoactive mediators. Prog. Cardiovase. Dis., 1996; 39:229-238.
18. Stroes ES, Koomans HA, de Bmin TWA, Rabelink TJ. Vascular function in the forearm of hypercholesterolaemic patients off and on lipid-lowering medication. Lancet, 1995; 346:467-471.
19. Chowienczyk PJ, Watts, GF, Cockroft JR, Ritter JM. Impaired endothelium - dependent vasodilation of forearm resistance vessels in hypercholesterolaemia. Lancet, 1992; 340: 1430-1432.
20. Casino PR, Kilcoyne CM, Quyyumi AA, Hoeg JM, Panza JA. The role of ot nitric oxide in endothelium-dependent vasodilation of hypercholesterolemic patients, Circulation, 1993, 88: 2541-2547.
21. Panza JA, Quyyumi AA, Brush JE, Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. New Engl. J. Med. 1990; 323:22-27.
22. Treasure CB, Manoukian SV, Klem JL. et al. Epicardial coronary artery response to acetylclioline are impared in hypertensive patients. Circ. Research 1992; 71:776-781.
23. Johnstone MT, Creager SL, Scales KM et al. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation, 1993; 88:2510-2516.
24. Ting HH, Timini FK, Boles KS el al. Vitamin C improves enoothelium-dependent vasodilatiiin in patients with non-insulin-dependent diabetes mellitus. J.Clin. Investig. 1996:97:22-28.
25. Zeiher AM, Schachinger V., Minnenf. Long-term cigarette smoking impairs endotheliu independent coronary arterial vasodilator function. Circulation, 1995:92:1094-1100.
26. Heitzer T., Via Herttuala S., Luoma J. et al. Cigarette smoking potentiates endothelial dislunction of forearm resistance vessels in patients with hypercholesterolemia. Role of oxidized LDL. circulation. 1996, 93: 1346-1353.
27. Tawakol A., Ornland T, Gerhard M. et al. Hyperhomocysteinemia is associated with impaired enaothcliurn - dependent vasodilation function in humans. Circulation, 1997:95:1119-1121.
28. Vallence P., Coller J., Moncada S. Infects of endothelium-derived nitric oxide on peripheial arteriolar tone in man. Lancet. 1989; 2:997-999.
29. Mayer B., Werner ER. In search of a function for tetrahydrobioptcrin in the biosynthesis of nitric oxide. Naunyn Schmiedebergs Arch Pharmacol. 1995: 351: 453-463.
30. Drexler H., Zeiher AM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolemic patients by L-arginine. Lancet, 1991; 338: 1546-1550.
31. Ohara Y, Peterson TE, Harnson DG. Hypercholesterolemia increases eiidothelial superoxide anion production. J.Clin. Invest. 1993, 91: 2546-2551.
32. Harnson DG, Ohara Y. Physiologic consequences of increased vascular oxidant stresses in hypercholesterolemia and atherosclerosis: Implications for impaired vasomotion. amer. J. Cardiol. 1995, 75:75B-81B.
33. Dzau VJ, Gibbons GH. Endothelium and growth factors in vascular remodeling of hypertension. Hypertension, 1991: 18 suppl. III: III-115-III-121.
34. Gibbons G.H., Dzau VJ. The emerging concept of vascular remodeling. New Engl. J. Med., 1994, 330: 1431-1438.
35. Ignarro LJ, Byrns RE, Buga GM, Wood KS. Endothelium derived relaxing factor from pulmonary artery and vein possesses pharmaciilogical and chemical properties identical to those of nitric oxide radical. Circul. Research. 1987; 61:866-879.
36. Palmer RMJ, Femge AG, Moncaila S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987, 327: 524-526.
37. Ludmer PL, Selwyn AP, Shook TL et al. Paradoxical vasoconstriction induced by acetylcholin in atherosclerotic coronary arteries. New Engl. J. Med. 1986, 315: 1046-1051.
38. Esther CRJr, Marino EM, Howard TE et al. The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice. J.Clin. Invest. 1997:99:2375-2385.
39. Lasher TF. Angiotensin, ACE-inhibitors and endothelial control of vasomotor tone. basic research. cardiol. 1993; 88(SI): 15-24.
40. Vaughan D.E. Endothelial function, fibrinolysis, and angiotensin-converting enzym inhibition. Clin. Cardiology. 1997; 20(SII): II-34-II-37.
41. Vaughan DE, Lazos SA, Tong K. Angiotensin II regulates the expresiion of plasminogen activator inhibitor-1 in cultured endothelial cells. J.Clin. Invest. 1995; 95:995-1001.
42. Ridker PM, Gaboury CL, Conlin PR et al. Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II. circulation. 1993; 87: 1969-1973.
43. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADH oxidase activity in cultured vascular smooth muscle cells. Circ. Res. 1994; 74:1141-1148.
44 Griendling KK, Alexander RW. Oxidative stress and cardiovascular discase. circulation. 1997; 96:3264-3265.
45Hamson DG. Endothelial function and oxidant stress. Clin. cardiol. 1997; 20(SII): II-11-II-17.
46. Kubes P, Suzuki M, Granger DN. Nitric oxide: An endogenous modulator of leukocyte adhesion. Proc. Natl. Acad. sci. USA., 1991; 88:4651-4655.
47. Lefer AM. Nitric oxide: Nature's naturally occurring leukocyte inhibitor. Circulation, 1997; 95: 553-554.
48. Zeiker AM, Fisslthaler B, Schray Utz B, Basse R. Nitric oxide modulates the expression of monocyte chemoat-tractant protein I in cultured human endothelial cells. Circ. Res. 1995; 76:980-986.
49. Tsao PS, Wang B, Buitrago R., Shyy JY, Cooke JP. Nitric oxide regulates monocyte chemotactic protein-1. circulation. 1997; 97:934-940.
50. Hogg N, Kalyanamman B, Joseph J. Inhibition of low-density lipoprotein oxidation by nitric oxide: potential role in atherogenesis. FEBS Lett, 1993; 334:170-174.
51. Kubes P, Granger DN. Nitric oxide modulates microvascular permeability. amer. J Physiol. 1992; 262: H611-H615.
52. Austin M. A. Plasma triglyceride and coronary heart disease. Artcrioscler. Thromb. 1991; 11:2-14.
53. Sarkar R., Meinberg EG, Stanley JC et al. Nitric oxide reversibility inhibits the migration of cultured vascular smooth muscle cells. Circ. Res. 1996:78:225-230.
54. Comwell TL, Arnold E, Boerth NJ, Lincoln TM. Inhibition of smooth muscle cell growth by nitric oxide and activation of cAMP-dependent protein kinase by cGMP. amer. J Physiol. 1994; 267:C1405-1413.
55. Kolpakov V, Gordon D, Kulik TJ. Nitric oxide-generating compounds inhibit total protein and collgen synthesis in cultured vascular smooth cells. Circul. Res. 1995; 76:305-309.
56. McNamara DB, Bedi B, Aurora H et al. L-arginine inhibits balloon catheter-induced intimal hyperplasia. Biochem. Biophys. Res. commun. 1993; 1993: 291-296.
57. Cayatte AJ, Palacino JJ, Horten K, Cohen RA. Chronicion inhibit of nitric oxide production accelerates neointima formation and impairs endothelial function in hypercholesterolemic rabbits. Arterioscler Thromb. 1994; 14:753-759.
58. Tarry WC, Makhoul RG. L-arginine improves endothelium-dependent vasorelaxation and reduces intimal hyperplasia after balloon angioplasty. Arterioscler. Thromb. 1994:14:938-943.
59 De Graaf JC, Banga JD, Moncada S et al. Nitric oxide functions as an inhibitor of platelet adhesion under flow conditions. Circulation, 1992; 85:2284-2290.
60. Azurna H, Ishikawa M, Sekizaki S. Endothelium-dependent inhibition of platelet aggregation. Brit. J Pharmacol. 1986; 88:411-415.
61. Stamler JS. Redox signaling: nitrosylation and related target interactions oi nitric oxide. Cell, 1994; 74:931-938.
62 Shah P.K. New insights in the pathogenesis and prevention of acute coronary symptoms. amer. J. Cardiol. 1997:79:17-23.
63. Rapoport RM, Draznin MB, Murad F. Endothelium-dependent relaxation in rat aorta may be mediated through cyclic GMO-depcndent protein phosphorviation Nature, 1983: 306: 174-176.
64. Joannides R, Haefeli WE, Linder L et al. Nitric oxide is responsible for flow-dependent dilation of human peripheral conduit arteries in vivo. Circulation, 1995:91:1314-1319.
65. Ludmer PL, Selwyn AP, Shook TL et al. Paradoxical vasoconstriction induced by acetylcholine in atlierosclerotic coronary arteries. New Engl. J. Mod. 1986, 315: 1046-1051.
66. Bruning TA, van Zwiete PA, Blauw GJ, Chang PC. No functional involvement of 5-hydroxytryptainine la receptors in nitric oxide dependent dilation caused by serotonin in the human forearm vascular bed. J. Cardiovascular Pharmacol. 1994; 24:454-461.
67. Meredith IT, Yeung AC, Weidinger FF et al. Role of impaired endotheliuin-dependent vasodilatioii in iscnemic manifestations from coronary artery disease. Circulation, 1993, 87(S.V): V56-V66.
68. Egashira K, Inou T, Hirooka Y, Yamada A. et al. Evidence of impaired endothclium-dependentonary vasodilation in patients with angina pectoris and normal coronary angiograins. New Engl. J. Mod. 1993; 328: 1659-1664.
69. Chilian WM, Eastham CL, Marcus ML. Microvascular distribution of coronary vascular resistance in beating left ventricle. amer. J Physiol. 1986; 251: 11779-11788.
70 Zeiher AM, Krause T, Schachinger V et al. Impaired endothelium-dependent vasodilation of coronary resistance vessels is associated with exercise-induced myocardial ischemia. circulation. 1995, 91: 2345-2352.
71. Blann AD, Tarberner DA. A reliable marker of endothelial cell dysfunction: does it exist? Brit. J. Haematol. 1995; 90:244-248.
72 Benzuly KH, Padgett RC, Koul S et al. Functional improvement precedes structural regression of atherosclerosis. Circulation, 1994; 89: 1810-1818.
73. Davis SF, Yeung AC, Meridith IT et al. Early endothelial dysfunction predicts the development of ottransplant coronary artery disease at I year posttransplant. Circulation 1996; 93:457-462.
74. Celemajer DS, Sorensen KE, Georgakopoulos D et al. Cigarette smoking is associated witn dose-related and potentially reversible iinpairment of endothelium-dependent dilation in healthy young adults. Circulation, 1993; 88:2140-2155.
75. Vogel RA, Coretti MC, Ploinic GD. Effect of single high-fat meal on endothelial hinction in healthy subject. amer. J. Cardiol. 1997; 79:350-354.
76. Azen SP, Qian D, Mack WJ et al. Effect of supplementary antioxidant vitamin intake on carotid arterial wall intima-media thickness in a controlled clinical trial of cholesterol lowering. Circulation, 1996:94:2369-2372.
77. Levine GV, Erei B, Koulouris SN et al. Ascorbic acid reverses endothelial vasomotor dysfunction in patients with coronary artery discase. Circulation 1996; 93:1107-1113.
78. Homing B., Maier V, Drexler H. Physical training improves endothelial function in patients with chronic heart failure. Circulation, 1996; 93:210-214.
79. Jensen-Urstad KJ, Reichard PG, Rosfors JS et al. Early atherosclerosis is retarded by improved long-term blood-glucose control in patients with IDDM. Diabetes, 1996; 45: 1253-1258.
80. Scandinavian Simvastatin Sunnval Study Investigators. Randomiseci trial cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Sinivastatin Survival Study (4S). Lancet, 1994; 344: 1383-1389.
81. Drexler H, Zeiher AM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolemic patients by L-arginine. Lancet, 1991; 338: 1546-1550.
82. Crcager MA, Gallagher SJ, Girerd XJ et al. L-arginine improves endothelium-dependent vasodilation in hypercholcsterolcrnic humans. J.Clin. Invest., 1992: 90: 1242-1253.
83. Tienfenhacher CP, Chilian WM, Mitchel M, DeFily DV. Restoration of endothclium-dependent vasodilation after reperliision injury by tetrahydrobiopterin. Circulation, 1996: 94: 1423-1429.
84. Ting HH, Timimi FK, Haley EA, Roddy MA et al. Vitamin C improves endothelium-dependent vasodilation in forearm vessels of humans with hypercholesterolemia. Circulation, 1997:95:2617-2622.
85. Ting HH, Timimi FK, Boles KS et al. Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J.Clin. Invest. 1996:97:22-28.
86. Heilzer T, Just H, Munzel T. Antioxidant vitamin C improves endothelial dysfunction in chronic smokers. Circulation, 1996:94:6-9.
87. Solzbach U., Hornig B, Jeserich M, Just H. Vitamin C improves endothelial ctysfubction of epicardial coronary arteries in hypertensive patients. Circulation, 1997:96:1513-1519.
88. Mancini GBJ, Henry GC, Macaya C. et al. Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dystunction in patients with coronary artery disease, the TREND study. Circulation, 1996: 94: 258-265.
89 Rajagopalan S, Harrison DG. Reversing endothelial dysfunction with ACE-inhibitors. A new TREND? Circulation, 1996, 94: 240-243.
90. Willix AL, Nagel B, Churchill V el al. Antiatherosclerotic effects of nicardipine and nifedipine in cholesterol-fed rabbits. Arteriosclerosis 1985:5:250-255.
91. Berk BC, Alexander RW. Biology of the vascular wall in hypertension. In: Renner R.M., ed. The Kidney. Philadelphia: W. B. Saunders, 1996: 2049-2070.
92. Kagami S., Border WA, Miller DA, Nohle NA. Angiotensin II stimulates extracellular matrix protein syntliesis through induction from transforming growth factor B in rat glomerular mesangial cells. J.Clin. Invest, 1994: 93: 2431-2437.
93. Frohlich ED, Tarazi RC. Is arterial pressure the sole factor responsible for hypertensive cardiac hypertropliy? amer. J. Cardiol. 1979:44:959-963.
94. Frohlich ED. Overview of hemoilynamic factors associated with left ventricular hypertrophy. J. Mol. cell. Cardiol., 1989: 21: 3-10.
95. Cockcroft JR, Chowienczyk PJ, Urett SE, Chen CP et al. Nebivolol vasodilated human forearm vasculature, evidence for an L-arginine/NO-dependent mccahanism. J Pharmacol. Expert. Ther. 1995, Sep; 274(3): 1067-1071.
96. Brehm BR, Bertsch D, von Falhis J, Wolf SC. Beta-blockers of the third generation inhibit endothelium-I liberation mRNA production and proliferation of human coronary smooth muscle and endothelial cells. J. Cardiovasc. Pharmacol. 2000, Nov: 36 (5 Suppl.): S401-403.

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

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, the study of embryos has 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 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 (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 noticeably 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, e.g. increase 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, immunocomplex, 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, encounter 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 endothelial dysfunction may be vasospasm and thrombosis). Treatment of endothelial dysfunction is aimed at restoring the dilatory vascular response.

Medications, potentially capable of affecting 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 compared with 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.

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 on 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”.

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.

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, 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.

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)