**5. Preeclampsia as a manifestation of excessive systemic inflammatory response, accompanied by endothelial activation/ dysfunction**

PE is a multisystemic pathologic condition, manifesting after the 20th week of pregnancy. PE clinical signs are: an increase of systolic blood pressure (SBP) above 140 mm Hg, diastolic blood pressure (DBP) above 90 mm Hg for the first time noted during pregnancy; proteinuria (≥0.3 g/L) in daily urine, edema, manifestation of multiorganic/polysystemic dysfunction/ insufficiency [133]. Severe PE is accompanied by acute renal failure, eclampsia, pulmonary edema, HELLP (hemolysis, elеvated liver enzymes, and lоw plаtelet соunt)-syndrome [3].

Etiology of PE is not clear; genetic, immunological and microenvironment may play a role [134–138]. Currently two phenotypic variations of PE are distinguished: early manifestation of the symptoms (before the 34th week of gestation) and later manifestation (after the 34th week of gestation) [139]. Pathophysiological mechanisms of PE development are distinguished accordingly [140]. The first—"fetal" pathway—is characterized by inadequate or microcellular invasion of trophoblast cells into the uterine spiral arteries and lack or incompleteness of the phase of substitution of placental smooth muscle elastic fibers with fibrinoid [140, 141]. In this mechanism, physiological remodeling and transformation of spiral arteries is lacking, and this affects the uterine-placentary blood flow quality [142–144]. Fetal mechanism of PE development presents with severe disease course and frequent complications in the neonate. The second pathway is "maternal", where the deficiency of uterineplacental blood flow appears as a result of spiral arteries damage due to certain maternal diseases, especially thrombophilias (genetic or acquired). In this case, the study of placental morphology testifies adequate gestational reorganization of spiral arteries. Maternal pathway usually implies later manifestation and a milder course. Some also distinguish the third (or "mixed") pathway, where the arteries are both affected and poorly reorganized [145, 146].

**5.1. Endothelium activation markers in preeclampsia**

HELLP, hemolysis, elеvated liver enzymes, and lоw plаtelet соunt.

Numerous studies have shown that in PE, manifestations of excessive SIR are observed due to the loss of control over the balance of production of pro/anti-inflammatory cytokines. This leads to an increase in the synthesis and expression of key molecules that mediate intercellular contacts between leukocytes and endothelium [147, 153, 154]. In this context, it has been shown that in PE, the plasma levels of sE-selectin, sVCAM-1 and sICAM-1 were significantly elevated [100, 155–157], and that cultivation of endothelial cells with the blood serum of PE women significantly increased the expression of ICAM-1 by the endothelial cells [158].

**Figure 1.** Modern concept of the pathogenesis of preeclampsia (PE). Two phenotypic PE variations (early onset-PE and late onset-PE) exhibit different pathophysiology and clinical outcome. Clinical manifestations of endothelial activation/ dysfunction are expressed in various degree and in both forms. SIR, systemic inflammatory response; BP, blood pressure;

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It was found that the expression of E-selectin and P-selectin in the endothelial cell culture was significantly higher after administration of trophoblast cells from the PE patients, than after cultivation of endothelial cells with trophoblast cells isolated from placental tissue of healthy women [159]. We have shown in a prospective longitudinal study that in patients with severe PE, the levels of sE-selectin, sVCAM-1 and sICAM-1 were increased from the 8th week of pregnancy until the appearance of clinical symptoms of the disease [160]. In a similar design study, it was shown that joint determination of sICAM-1 and sVCAM-1 levels measured in peripheral blood within 22–29 weeks of gestation, was of high predictive value and capable to detect up to 55% of women with a pathologic pregnancy [161]. The increased levels of sICAM-1 and sVCAM-1 in blood during PE significantly correlated with the signs of the acute phase of inflammation and PE: hypertension, proteinuria, increase of hepatic enzymes levels

Disrupted trophoblast invasion initiates ischemic and hypoxic damage of placental cells and tissues, leading to increase of cell debris and microparticles of fetal origin contents in the mother's blood. These processes result in the mother's immune cells activation and inflammatory cytokines synthesis induction [147], leading to the development of generalized endothelial activation/dysfunction with development of multiorganic insufficiency [148] (**Figure 1**). Trophoblast debris was also found in the mother's is blood in a normal pregnancy and it was primarily apoptotic. Particles of trophoblast debris range from polynuclear aggregates of the syncytium cells to subcellular micro and nanoparticles. *In vitro* co-culturing of trophoblast debris, obtained from women with normal pregnancy, with macrophages and endothelial cells leads to tolerogenic М2-phenotype of macrophages [149, 150]. Trophoblast debris becomes more necrotic when *in vitro* system is supplemented with antiphospholipid antibodies or IL-6. Phagocytosis of the necrotic debris by the endothelial cells is accompanied by their activation [151]. Activation of endothelial cells is also caused by the addition of the trophoblast debris isolated from patients with preeclampsia to the culture of the endothelial cells [152].

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**Figure 1.** Modern concept of the pathogenesis of preeclampsia (PE). Two phenotypic PE variations (early onset-PE and late onset-PE) exhibit different pathophysiology and clinical outcome. Clinical manifestations of endothelial activation/ dysfunction are expressed in various degree and in both forms. SIR, systemic inflammatory response; BP, blood pressure; HELLP, hemolysis, elеvated liver enzymes, and lоw plаtelet соunt.

#### **5.1. Endothelium activation markers in preeclampsia**

**5. Preeclampsia as a manifestation of excessive systemic** 

128 Endothelial Dysfunction - Old Concepts and New Challenges

**dysfunction**

[145, 146].

endothelial cells [152].

**inflammatory response, accompanied by endothelial activation/**

PE is a multisystemic pathologic condition, manifesting after the 20th week of pregnancy. PE clinical signs are: an increase of systolic blood pressure (SBP) above 140 mm Hg, diastolic blood pressure (DBP) above 90 mm Hg for the first time noted during pregnancy; proteinuria (≥0.3 g/L) in daily urine, edema, manifestation of multiorganic/polysystemic dysfunction/ insufficiency [133]. Severe PE is accompanied by acute renal failure, eclampsia, pulmonary edema, HELLP (hemolysis, elеvated liver enzymes, and lоw plаtelet соunt)-syndrome [3].

Etiology of PE is not clear; genetic, immunological and microenvironment may play a role [134–138]. Currently two phenotypic variations of PE are distinguished: early manifestation of the symptoms (before the 34th week of gestation) and later manifestation (after the 34th week of gestation) [139]. Pathophysiological mechanisms of PE development are distinguished accordingly [140]. The first—"fetal" pathway—is characterized by inadequate or microcellular invasion of trophoblast cells into the uterine spiral arteries and lack or incompleteness of the phase of substitution of placental smooth muscle elastic fibers with fibrinoid [140, 141]. In this mechanism, physiological remodeling and transformation of spiral arteries is lacking, and this affects the uterine-placentary blood flow quality [142–144]. Fetal mechanism of PE development presents with severe disease course and frequent complications in the neonate. The second pathway is "maternal", where the deficiency of uterineplacental blood flow appears as a result of spiral arteries damage due to certain maternal diseases, especially thrombophilias (genetic or acquired). In this case, the study of placental morphology testifies adequate gestational reorganization of spiral arteries. Maternal pathway usually implies later manifestation and a milder course. Some also distinguish the third (or "mixed") pathway, where the arteries are both affected and poorly reorganized

Disrupted trophoblast invasion initiates ischemic and hypoxic damage of placental cells and tissues, leading to increase of cell debris and microparticles of fetal origin contents in the mother's blood. These processes result in the mother's immune cells activation and inflammatory cytokines synthesis induction [147], leading to the development of generalized endothelial activation/dysfunction with development of multiorganic insufficiency [148] (**Figure 1**). Trophoblast debris was also found in the mother's is blood in a normal pregnancy and it was primarily apoptotic. Particles of trophoblast debris range from polynuclear aggregates of the syncytium cells to subcellular micro and nanoparticles. *In vitro* co-culturing of trophoblast debris, obtained from women with normal pregnancy, with macrophages and endothelial cells leads to tolerogenic М2-phenotype of macrophages [149, 150]. Trophoblast debris becomes more necrotic when *in vitro* system is supplemented with antiphospholipid antibodies or IL-6. Phagocytosis of the necrotic debris by the endothelial cells is accompanied by their activation [151]. Activation of endothelial cells is also caused by the addition of the trophoblast debris isolated from patients with preeclampsia to the culture of the Numerous studies have shown that in PE, manifestations of excessive SIR are observed due to the loss of control over the balance of production of pro/anti-inflammatory cytokines. This leads to an increase in the synthesis and expression of key molecules that mediate intercellular contacts between leukocytes and endothelium [147, 153, 154]. In this context, it has been shown that in PE, the plasma levels of sE-selectin, sVCAM-1 and sICAM-1 were significantly elevated [100, 155–157], and that cultivation of endothelial cells with the blood serum of PE women significantly increased the expression of ICAM-1 by the endothelial cells [158].

It was found that the expression of E-selectin and P-selectin in the endothelial cell culture was significantly higher after administration of trophoblast cells from the PE patients, than after cultivation of endothelial cells with trophoblast cells isolated from placental tissue of healthy women [159]. We have shown in a prospective longitudinal study that in patients with severe PE, the levels of sE-selectin, sVCAM-1 and sICAM-1 were increased from the 8th week of pregnancy until the appearance of clinical symptoms of the disease [160]. In a similar design study, it was shown that joint determination of sICAM-1 and sVCAM-1 levels measured in peripheral blood within 22–29 weeks of gestation, was of high predictive value and capable to detect up to 55% of women with a pathologic pregnancy [161]. The increased levels of sICAM-1 and sVCAM-1 in blood during PE significantly correlated with the signs of the acute phase of inflammation and PE: hypertension, proteinuria, increase of hepatic enzymes levels [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 from the umbilical cord after birth [163].

keys to PE, which is less studied, but exhibits similar clinical signs. Experimental models allow to evaluate not only the degree of the eGC damage by various factors (SIR being the most significant), but also the molecular changes of the eGC composition. This moment is a crucial point because SIR is not a specific process; it accompanies almost any pathology and promotes the generation of neoantigens, acting as an adaptive response trigger and provok-

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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 indi-

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

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 com-

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 pro-

We thank Alexey Komarovsky and Natalia Baranova for their help in the manuscript

cator of endothelial injury and a potential marker of vascular injury.

partment—the eGC, which regulates the functions of the endothelium.

the difficulties of eGC visualization and diagnosis.

gression of endothelial dysfunction.

**Acknowledgements**

preparation.

ing autoimmune reactions.

**6. Conclusion**
