**4. Endothelial activation and endothelial dysfunction**

binding mainly to N-acetyllactosamine. The main ligands are Galβ1-3GlcNAc- or Galβ1- 4GlcNAc- [115]. Galectins are involved in many cell activities: cell cycle regulation, migration, cell signals transmission, effectory functions, apoptosis, immunoregulation [116]. Galectins may regulate inflammatory reaction both positively (Gal-3, Gal-8, Gal-9) and negatively (Gal-1). The endothelium may be a source of Gal-1, which then targets the neutrophils to inhibit cell

C. Siglecs are a family of 17 known lectins, which specifically bind the glycans structures with terminal sialic acid [117]. Sialyl Tn (Neu5Acα2,6GalNAcα-) is a common ligand for all

selectin-dependent cell adhesion [118]. The majority of this family members are inhibitory receptors as they bear an immunoreceptor tyrosine-based inhibition motif (ITIM) in their structure, and they are mainly expressed on immune cells [119]. Siglecs participate in regulation/restriction of an excessive activation response to inflammatory reaction, initiated via recognition of pathogen associated molecular patterns, and damage-associated molecular patterns, with following phagocytosis of cells, bearing these patterns [120, 121]. Siglecs regulate cell proliferation, differentiation, apoptosis, adhesion, cytokines synthesis and negative

Some endogenous lectins are capable, like autoantibodies, to interact with the body's unchanged antigens (glycans), so-called own self-images (SAMPs-self-associated molecular patterns) [111]. Molecular patterns, containing sialic acid and heparin/HS are supposed to act as self-images [111]. Also it is thought that interaction of lectins, recognizing SAMPs, (mainly siglecs), with ligands, inhibits the immune response to foreign/damaging effects [111, 120].

It is known that presence of terminal sialic acid is very important: this substance provides the overall negative charge of cell surface, glycoconjugates conformation stabilization, production of glycoconjugates, and cells protection from recognition and degradation. Sialylation protective properties manifest not only with sialylated structures interaction with inhibited receptors, but also with masking of sugar residues which are the antigen determinants [123, 124]. For example, at desialylation, the unmasked residues of Galβ-, GalNAc-, and mannose, interacting with lectins from galectins family and С-type lectins [120];

Therefore, inflammatory response regulation is implemented under direct involvement of the glycan binding proteins (endogenous lectins) and glycans; composition and structure of these vary significantly under physiological and pathophysiological conditions, providing evidence of the eGC modification at inflammation, and of formation of the carbohydrate "zip code", which acts as navigator for immune cells. Inflammatory reactions in pregnancy are initiated by pathogenic and danger images, which are formed at the fetal-mother cell contact; this activates innate and adaptive immunity. SIR may be enhanced or restricted through mechanisms based on carbohydrate-protein interaction [125–127]. Excessive SIR developing in pathologic pregnancy is characterized by compensatory reactions and development of various dysfunc-

these interactions are important for metastasis and SIR development.

tions, resulting in organic or multi-organic failure [128].

is a ligand for Siglec-8, and is important for

recruitment, аnd Gal-3, Gal-8, Gal-9 promote neutrophil and eosinophil adhesion [89].

members of this family. Glycan 6′ sulfated SLe<sup>x</sup>

126 Endothelial Dysfunction - Old Concepts and New Challenges

regulation of В-lymphocyte signaling [122].

As a rule, in the studies dedicated to determination of endothelium role in different pathologies, the authors use terms "endothelial activation" and "endothelial dysfunction" [129]. Activation should be distinguished from activity because in its resting state, endothelium is a metabolically active organ, which produces vasodilatory substances and bears anticoagulative and antiadhesive phenotype. Activation of endothelium under various pathophysiologic processes leads to alterations of its phenotype and function. These events may be reversible, but also may cause multiorgan failure.

There are two stages in endothelial activation: endothelial stimulation (early events) and endothelial activation (later events). The latter can be subdivided in endothelial activation of types I and II, respectively [130, 131]. Endothelial activation of type I follows the stimulation stage and manifests with shedding of the adhesion molecules and molecules with antithrombotic properties, such as Р-selectin, thrombin, heparin, antithrombin ІII and thrombomodulin, from the surface of the endothelial cells. In the same time, the endothelial cells of the venules and small veins decrease in volume, and the contacts between the cells become distorted, resulting in hemorrhages, edema, and increase of vessels permeability [131]. Endothelial activation of type II is a slightly delayed process, which depends on gene transcription activation and protein synthesis *de novo*. As a result, the genes coding for the adhesion molecules, chemokines and procoagulative factors: Е-selectin, vWF, IL-8, thrombocytes activating factor [132], are activated. Also, the secretion of NO and prostacyclin increases. Morphologic changes show protrusion of the endothelial cells into the vessel lumen, cell hypertrophy and an increase of cell permeability. The result of this stage is leukocyte contact with activated endothelium through lectin-carbohydrate interactions, extravasation, transendothelial migration, and, possibly, leucocyte binding with Fc-receptors (FcR) of endothelial cells with immune complexes disposition [131]. Alterations of phenotype, accompanying endothelial cells activation, manifest also with the change of the carbohydrate composition of the molecules forming the eGC.

Therefore, endothelial activation implies an alteration of the endothelial cells phenotype under the activation factors (cytokines, endotoxins, etc.) impact, inducing shedding and modification of the vasculoprotective surface layer associated with the membrane, and expression of the activation antigens. This correlates with pro-adhesive, antigen-presenting and procoagulative properties of the endothelial cells. Activation reflects an ability of endothelial cells to perform new functions, but this status does not presume a cell damage or their uncontrolled division. Endothelium activation is a reverse process with a possibility to return to a state of active reposing cells [131].

Endothelium dysfunction, on the other hand, is a stage following the endothelium activation and manifesting with cell functional activity change; it leads to loss of the ability of endothelium to perform its function, and to a disbalance of factors, which provide homeostasis and a normal course of all processes, mediated by endothelium [8, 129, 131]. Endothelial dysfunction is a consequence of chronic, permanent endothelial activation and may lead to non-reversible damage of the endothelial cells, their apoptosis and necrosis.
