**6. Conclusion**

[162]. Also it was noted that high levels of sVCAM-1 and sE-selectin in women with PE could result in adverse perinatal outcome and endothelial dysfunction in fetus, as confirmed by negative correlation between sVCAM-1 and endogenous NO synthesis by HUVECs, isolated

The signs of endothelial activation are the expression of activation markers by endothelial cells and increased plasma concentrations of the soluble forms of CAMs and of the factors, regulating angiogenesis and blood clotting. However, the main feature of the evolving endothelial activation is alteration, damage and shedding of the eGC and an increase of its components concentration in blood. Currently, there are limited studies of this phenomena in PE, but available reports show significant alteration of eGC composition in the placental structures in PE [164]. The most prominent alteration of the eGC composition was found in the placentas of women with severe PE. Alterations take place also in the eGC capillaries of terminal placental villi: the content of glycans with terminal β-galactosyl and α-mannosyl residues increase, while the content of α2,3-linked sialic acids decrease in the glycome in severe PE [165]. These alterations are supposed to point to the exposure of glycans bearing the "danger signals" and being the counter-receptors for endogenous lectins; interaction with these activate maternal immune system [166, 167] (REF). Such studies, performed by immunohistochemistry of placenta after childbirth and using the lectins panel or monoclonal antibodies to carbohydrates antigens, give an idea of alterations of the placental glycome and its separate structures, including capillary endothelium, and provide evidence obtained by direct eGC visualization [165, 168]. Since direct visualization of the eGC is impossible in clinical trials where no surgical tissue sampling is implied, in these cases, an indirect assessment

Indirect methods have significant limitations, but they are the only possibility to evaluate the eGC *in vivo*. Indirect assessment of the eGC by ELISA show that in PE, the plasma content of the structural proteoglycans (endocan-1, syndecan-1, decorin and HA) and the GAGs of eGC increase [169–171]. Serum endocan concentrations were significantly elevated in women with PE versus normotensive controls, and concentrations seem to be associated with the severity of the disease [172]. Median maternal plasma endocan concentrations were higher in PE patients and lower in acute pyelonephritis with bacteremia than in uncomplicated pregnancy. No significant difference was observed in the median plasma endocan concentration between other obstetrical syndromes and uncomplicated pregnancies [173]. It is suggested that in PE, the maternal endothelium is a source of GAGs in blood, and intensive eGC shedding thus indicates a manifestation of endothelial dysfunction [169–174]. Also, patients with PE show GAGs excretion in urine; this is thought to be linked with the eGC proteoglycans alterations and with the glomerular basement membrane changes, and associated with proteinuria [175]. *In vitro* and *in vivo* experimental studies, using cell and animal models is another opportunity of indirect eGC evaluation. This approach was used to study CKD [74, 75], cardio-vascular and inflammatory diseases [13, 176], cancer [13, 176, 177]—the conditions manifestating with hypertension, proteinuria, edema, SIR, thrombosis. The results of such studies provide some

from the umbilical cord after birth [163].

130 Endothelial Dysfunction - Old Concepts and New Challenges

**5.2. Alteration of endothelial glycocalyx in preeclampsia**

of the content of the degradation products of eGC is used.

Endothelial dysfunction represents the central link in the pathogenesis of various diseases and complications, and is a subject of intensive research. On the background of the progress in understanding the mechanisms of development, diagnosis and treatment of endothelial dysfunction, many studies in the recent years have been focused on the eGC as an early indicator of endothelial injury and a potential marker of vascular injury.

Alterations of the phenotype of endothelial cells, secretion and release of various activation markers into the bloodstream and dysfunction of the endothelium are directly related to the damage of eGC. This damage is the initiating factor and the initial stage in the development of endothelial activation/dysfunction, but this stage has for a long time been obscure due to the difficulties of eGC visualization and diagnosis.

By now, the main criteria for eGC damage assessment have been defined. In addition to the appearance of eGC components in the blood, the degree of manifestation of the SIR is also an important criterium of the damage, since endothelial inflammation and dysfunction are inseparably related processes. In this regard, the molecular mechanism of the inflammatory reaction is based on the ligand-receptor, carbohydrate-protein interaction of the immune cells and endothelium, and alteration of glycome/glycocalyx is a crucial factor in the development of inflammation and endothelial dysfunction. Therefore, the pathogenesis of endothelial activation/dysfunction should be envisioned from the point of damage of the intravascular compartment—the eGC, which regulates the functions of the endothelium.

Expanding research of the eGC role in the development of endothelial dysfunction may be a subject of new discoveries in the pathogenesis of a large group of diseases, including pregnancy pathology and PE, especially since PE is a classic example of the immune system hyperactivation, manifestation of SIR and development of endothelial dysfunction. Undoubtedly, future studies of the eGC will evoke an absolutely new insight in the development and progression of endothelial dysfunction.
