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Endothelium - vascular intima. It performs a number of important functions, including: it regulates the tone of blood vessels, contributes to a change in their diameter, is a sensor of damage to the vascular wall, and can trigger the blood coagulation mechanism.

1. General plan of the structure of the vascular wall.

2. Main functions of the vascular endothelium.

• Regulation of vascular tone and vascular resistance
• Regulation of blood flow
• Regulation of angiogenesis
• Implementation of the inflammation process

3. The main functions of the endothelium are implemented:

1) A shift in the secretory function of the endothelium towards vasodilating factors (90% is nitric oxide).

2) Inhibition:

• Platelet aggregation
• Adhesion of white blood cells
• Proliferation of smooth muscles

The main functions of the endothelial layer of a vascular cell are determined by its synthetic phenotype - a set of vasoactive factors synthesized by the endothelium.

4. With endothelial dysfunction, there is:

1) Shift of the secretory function of the endothelium towards vasoconstrictor factors

2) Gain:

• platelet aggregation
• adhesion of white blood cells
• proliferation of smooth muscle cells

Which leads to a decrease in the vascular lumen, thrombosis, the appearance of a focus of inflammation and hypertrophy of the vascular wall.

5. Regulation of blood flow with the participation of the endothelium is normal.

6. Shift of the synthetic activity of the endothelial cell towards the procoagulant phenotype in case of violation of the integrity of the endothelium or the occurrence of an inflammatory process.

7. VASCULAR ENDOTHELIUM SYNTHESES AND RELEASES CONTRACTING AND DILATIVE VASOACTIVE FACTORS:

8. Types of action of vasoactive factors synthesized by the endothelium of the vascular wall.

9. Main pathways of arachidonic acid metabolism.

Cyclooxygenase pathway
Lipoxygenase pathway
Epoxygenase pathway
Transacylase (membrane) pathway

Activation of phospholipase A2 (bradykinin) stimulates the release of arachidonic acid into the soluble part of the cell and its metabolism

10. Cooperative method of activation of arachidonic acid.

11. Metabolism of arachidonic acid (AA) with the participation of phospholipase A2 (PLA2).

==>>Inflammation.

12. Metabolites of arachidonic acid via the cyclooxygenase pathway.

13. Mechanism of action of non-steroidal anti-inflammatory drugs with analgesic action.

14. Types of cyclooxygenases. Their stimulation and inhibition.

Cyclooxygenase type I (inhibited by paracetamol) and type II (inhibited by diclofenac)

15. The mechanism of realization of the action of prostacyclin (PG2) on the smooth muscle of the vessel.

16. Scheme for the synthesis of endogenous cannabinoids.

Endogenous cannabinoids (NAEs) - (anandamide) are metabolized with the formation of arachidonic acid and its subsequent degradation.

The mechanism of action of the endogenous cannabinoid - anandamide on the vascular wall:

Rapid degradation in the endothelium reduces the expansive potential of endocannabinoids.

The effect of anandamide on the resistance of the perfused vascular bed of the intestine (A) and the isolated resistive mesenteric vessel (B).

Scheme of a possible pathway of anandamide metabolism inhibiting its direct vasodilator action on vascular smooth muscle.

17. Endothelium-dependent vasodilation.

Synthesis of nitric oxide: a key element is NO-synthase (constitutive - always works and inducible - activated under the influence of certain factors)

18. NO-synthase isoforms: neuronal, inducible, endothelial and mitochondrial.

The structure of nitric oxide synthases isoforms:

mtNOS is the alpha form of nNOS, characterized by a phosphorylated C-terminus and two altered amino acid residues.

19. The role of NO-synthases in the regulation of various body functions.

20. Scheme of activation of NO and cGMP synthesis in endothelial cells.

21. Physiological and humoral factors activating the endothelial form of NO-synthase.

Factors determining the bioavailability of nitric oxide.

Participation of nitric oxide in the oxidative stress response.

Influence of pyroxynitrite on proteins and cell enzymes.

22. Synthesis of nitric oxide by the endothelial cell and the mechanism of expansion of vascular smooth muscle.

23. Guanylate cyclase - an enzyme catalyzing the formation of cGMP from GTP, structure and regulation. The mechanism of vessel expansion with the participation of cGMP.

24. Inhibition of cGMP Rho-kinase pathway of vascular smooth muscle contraction.

25. Vasoactive factors synthesized by the endothelium and ways to implement their effects on vascular smooth muscle.

26. Discovery of endothelin, an endogenous peptide with vasoactive properties.

Endothelin is an endogenous peptide synthesized by endothelial cells of the vascular system.

Endothelin is a 21-mer peptide with vasoconstrictor properties.

Structure of endothelin-1, Family of endothelins: ET-1, ET-2, ET-3.

Endothelin:

Expression of different forms of the peptide in tissues:

• Endothelin-1 (vascular endothelium and smooth muscle, cardiac myocytes, kidney, etc.)
• Endothelin -2 (kidney, brain, intestinal tract, etc.)
• Endothelin-3 (intestine, adrenal glands)

Mechanism of synthesis in tissues: three different genes
Preproendothelin-->big endothelin-->endothelins
*furin-like endopept. endothelinconversion farms.
(cellular surface, intracl. vesicles)
Types of receptors and effects:
Eta (smooth muscle - contraction)
Etv
Content in tissues and blood: fm/ml
2-10 times increase in heart failure, pulmonary hypertension, renal failure, subarachnoid hemorrhage, etc.

27. Synthesis of endothelin by endothelial cells and mechanism of vascular smooth muscle contraction.

28. The mechanism of realization of the action of endothelin on the smooth muscle of the vessel in normal and pathological conditions.

29. Pathological role of endothelin.

• vasoconstriction
• hypertrophy
• fibrosis
• inflammation

30. The main factors of humoral regulation of vascular tone, mediating their action through changes in the secretory function of the endothelium.

• Catecholamines (adrenaline and norepinephrine)
• Angiothesin-renin system
• Endothelin family
• ATP, ADP
• Histamine
• Bradykinin
• Thrombin
• Vasopressin
• Vasoactive intestinal peptide
• Colcitonin gene-binding peptide
• Natriuretic peptide
• Nitrogen oxide

Characterization of the endothelium

The endothelium lines the heart, blood vessels and lymphatic vessels. It is a single-layer squamous epithelium of mesenchymal origin. Endothelial cells have a polygonal shape, usually elongated along the course of the vessels, and are connected to each other by tight and gap junctions. The total mass of all endotheliocytes in the human body is about 1 kg, and the total surface is more than 1000 sq.m. The cytoplasm of endotheliocytes is thinned to 0.2 - 0.4 microns and contains a large number of transport vesicles that can form transendothelial channels. Organelles are few, localized around the nucleus. The cytoskeleton is characterized by vimentin intermediate filaments. In endotheliocytes, special rod-shaped structures are found - Weibel-Palade bodies, containing factor VIII of the blood coagulation system.

Under physiological conditions, the endothelium is updated slowly.

Functions of the endothelium:

transport function- selective bilateral transport of substances between blood and other tissues is carried out through the endothelium;

hemostatic function The endothelium plays a key role in blood clotting. Normally, intact endothelium forms an athrombogenic surface. The endothelium produces procoagulants and anticoagulants;

vasomotor function- endothelium is involved in the regulation of vascular tone, releases vasoconstrictor and vasodilator substances;

receptor function- endothelial cells have receptors for various cytokines and adhesive proteins; they express on the plasmolemma a number of compounds that provide adhesion and subsequent transendothelial migration of blood leukocytes;

secretory function- endotheliocytes produce mitogens, growth factors, cytokines that regulate hematopoiesis and mediate inflammatory reactions;

vascular function- endothelium provides angiogenesis (both in embryonic development and during regeneration).

The second type of cells in the capillary wall is pericytes (Rouget cells) . These connective tissue cells have a process shape and surround the blood capillaries in the form of a basket, located in the cleavages of the basement membrane of the endothelium.

The third type of cells in the capillary wall is adventitial cells . These are poorly differentiated cells located outside of pericytes. They are surrounded by an amorphous substance of connective tissue, which contains thin collagen fibers. Adventitial cells are cambial pluripotent precursors of fibroblasts, osteoblasts, and fat cells.

Classification of capillaries

According to structural and functional features, there are three types of capillaries: somatic, fenestrated and sinusoidal, or perforated.

The most common type of capillaries is somatic. In such capillaries, there is a continuous endothelial lining and a continuous basement membrane. Capillaries of the somatic type are found in the muscles, organs of the nervous system, in the connective tissue, in the exocrine glands.

The second type - fenestrated capillaries. They are characterized by a thin endothelium with pores in the endotheliocytes. The pores are tightened by the diaphragm, the basement membrane is continuous. Fenestrated capillaries are found in endocrine organs, in the intestinal mucosa, in brown adipose tissue, in the renal corpuscle, and in the choroid plexus of the brain.

The third type - perforated capillaries, or sinusoids. These are capillaries of large diameter, with large intercellular and transcellular pores (perforations). The basement membrane is discontinuous. Sinusoidal capillaries are characteristic of the hematopoietic organs, in particular for the bone marrow, spleen, and also for the liver.

1 - endotheliocyte; 2 - basement membrane; 3 - fenestra; 4 - cracks (pores); 5 - pericyte; 6 - adventitial cell; 7 - contact of endotheliocyte and pericyte; 8 - nerve ending.

October 30, 2017 No comments

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

1. Intima, i.e. inner shell, includes the endothelium, a thin subendothelial layer, and an internal elastic membrane at the border with the median membrane. 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 broken under various physical influences, and restoration occurs due to the mitotic division of endotheliocytes under the influence of certain stimuli from the surrounding connective tissue and endotheliocytes.

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 - outer shell 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 adventipia is the presence in it of nerve endings and vasa vasorum - vessels that feed the wall of the arteries. Elastic fibers create resistive resistance, which increases with increasing blood pressure and thus counteracts the expansion of the vessel.

Elastic resistance determines the basal component of vascular tone - this is a phylogenetically ancient mechanism of autoregulation of vascular tone, which ensures 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 an active tension of 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 ratio between the basal and vasomotor components of vascular tone is different in different organs and tissues.

Smooth muscle and endothelial cells are of the greatest importance for the functioning of blood vessels. Particular attention in modern medicine attracts the endothelium, which, as it turned out, is able to synthesize a very wide range of biologically active substances at the border "blood - cells of tissues / organs" and thus perform the function of a "customs officer" at this border.

Endothelium - endocrine organ of the cardiovascular system

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

The structural organization of the endothelial lining is not the same 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 disordered arrangement of endotheliocytes, and in the second, endotheliocytes 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), the organ or tissue that they supply with blood.

Endothelial cells are also heterogeneous in their structure, which depends mainly on the fibrils of the cytoskeleton: active microfilaments, microtubules, intermediate filaments. These three types of fibrils, present in all cells, form various options microarchitecture of endothelium ion exchangers. Typical differences in cell architectonics 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 architectonics of endotheliocytes can be radically rebuilt 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 denoted by the term "reprogramming".

This process is attracting more and more attention in the aspect of modern understanding of the pathogenesis of various forms of pathology. The heterogeneity of endotheliocytes is expressed not only in structural features, but also in their genetic and biosynthetic specificity. For example, endotheliocytes of coronary, pulmonary and cerebral vessels, despite their histological similarity, differ significantly in the types of expressed receptors, the spectrum of synthesized biologically active molecules: enzymes, regulatory proteins, messenger proteins. Such heterogeneity predetermines the unequal participation of different populations of endotheliocytes 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 endotheliocytes is based on their ability to synthesize biologically active substances, which are, for the most part, functional antagonists. The set of these substances includes vasoconstrictors and vasodilators, proaggregants and antiaggregants, procoagulants and anticoagulants, mitogens and antimitogens.

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

The endothelial lining is under constant "pressure" of extra- and intravascular factors, which, in fact, are regulators of the "hormonal response" of endotheliocytes.

At the end of the last century, two types of response of endotheliocytes to disturbing influences were identified: one of them develops immediately (without changes in 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 endotheliocyte granules); the other - manifests itself 4-6 hours after the onset of the perturbing stimulus and is characterized by a change in the activity of genes that determines the de novo synthesis of adhesive molecules (for example: E-selekgan, ICAM-1, VCAM-1; interleukins IL-1 and IL-6; chemokines - IL-8, MCP-1 and other substances).

In a generalized form, 3 main groups of factors inducing the “hormonal response” of the endothelium can be distinguished.

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" (English, "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 adherent and aggregated platelets: thromboplastin, fibrinogen, von Willebrand factor, platelet growth factor, fibronectin, serotonin, ADP, acid hydrolases, as well as products of leukocytes that have moved to the marginal, parietal position (before total neutrophils), which at the same time become intensive producers of adhesive molecules, lysosomal proteases, reactive oxygen species, leukotrienes, group E prostaglandins, 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 in the conditions of development of various diseases is associated primarily with a significant change in the "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 the elastic deformation of a solid body 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 the blood vessel creates a “tensile (pressure dependent) shear stress” in its wall directed tangentially to the circumference of the vessel, and the blood velocity 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 affected by blood viscosity. It has been established that the arteries regulate their lumen in accordance with the change in this property of the blood: with an increase in viscosity, the vessels increase their diameter, and with a decrease, they decrease it.

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

Concerning the mechanisms of implementation of changes in shear stress, first of all, the question arises about the ability of endotheliocytes 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. for the synthesis and isolation of NO.

It was also found that endotheliocytes (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 stresses. It turned out that drugs that increase the content of intracellular cAMP can prevent such orientation.

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, the position on the active role of the endothelium in the regulation and disorders of blood circulation has assumed the character of a paradigm.

Physiological (moderately pronounced) 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 (by intensity or duration) changes in hemodynamic parameters, mainly blood flow and pressure, are accompanied by depletion or inadequate use of endothelial functionality, i.e., the development of endothelial dysfunction.

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.

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 specific mechanism actions.

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 of 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 of vascular smooth muscle 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.

With all the versatility of NO effects, Dzau et Gibbons managed to schematically formulate the main clinical consequences of chronic NO deficiency in the vascular endothelium, thereby showing the real consequences of DE on the model of coronary heart disease 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 are strong indications 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 of the brachial artery using acetylcholine or serotonin infusion, or using veno-occlusive plethysmography, as well as with the help of 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 may 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 the thickening of the intima of the carotid artery. Physical activity improves the condition of the endothelium even in heart failure.

Improving 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, a 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, ischemic heart 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 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 associated primarily with a deficiency in NO synthesis, the most important factor-regulator of vascular tone, but an even more important factor on which structural changes vascular wall.

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.

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The endothelium is just one layer of special cells that line the inside of the blood and lymphatic vessels, the cavities of the heart. Its functions support a huge number of body processes, many of which are vital. Many diseases, the root causes of which today not many doctors can find out, lie precisely in endothelial dysfunctions. In this article, read what the endothelium is for, what ailments it causes, and how they can be prevented or treated more effectively.

What is the endothelium for?

The endothelium belongs to the endocrine system. In specialized literature, it is designated as the most big organ. If the skin covers only the outer surface of the body, then the endothelium is scattered throughout all organs.

On the one hand, the endothelium is a protective layer in the structure of the walls of blood vessels and the heart. And on the other hand, it produces the substances necessary to maintain the following processes in the norm:

• blood clotting control,
• regulation of vascular tone,
• regulation blood pressure,
• maintenance of filtering kidney function,
• maintaining the ability of the heart to contract,
• maintaining normal metabolism in the brain.

Also, the endothelium continuously produces a large number of other biologically active substances. And besides that, he takes an important part in the work immune system . From this point of view, it belongs to the lymphatic system.

How is the endothelium arranged?

Endothelial cells are epithelial cells that are of mesenchymal origin. They are very tightly connected to each other and create a continuous structure that can be called monolithic. If you collect the entire endothelium of an adult, then it will be from one and a half to two kilograms.

What diseases are associated with deviations from the norm in the state and functions of the endothelium

Some diseases are causes and some are effects. In the case when the disease was the result of some other abnormal processes in the body, find real reason is not easy. One of these cases is diseases associated with disorders of the state and functions of the endothelium.

As mentioned above, the endothelium supports many functions with the substances it produces. Consequently, any deviations from the norm in his work are the causes of many diseases. Below is a list of them:

• spikes in abdominal cavity, atherosclerosis, asthma and other pathologies of the respiratory system, hypertension, disorders endocrine system at an older age, coronary insufficiency, any metabolic disorders, myocardial infarction, kidney failure, diabetes, insulin resistance.

If you have one of the above diagnoses, then pharmacy treatment will not help you achieve maximum improvement, let alone complete recovery. Because such a problem as endothelial disorders, doctors do not treat. In order to improve your health with these diagnoses, it is necessary, first, to eliminate their causes, namely, to restore the integrity and functions of the endothelium.

NPCRIZ offers a wide range of . And along with them, the functions of the endothelium are restored. You can also support the endothelium and .