**1. Introduction**

Adequate formation of uteroplacental and fetal placental blood flow is the determining factor of physiological pregnancy and fetal development. Successful uterine‐placental vascular morphogenesis and embryonic morphogenesis of fetal blood system are the basis of these processes. There are two stages of vascular morphogenesis: vasculogenesis—primary forma‐ tion and development of blood vessels *de novo* from committed mesodermal cells—and angio‐ genesis—formation of new blood vessels from existing vascular structures, which reflect the formation of vascular system of a fetus and placenta during pregnancy [1–4].

"Early pregnancy" period includes several time intervals when the most significant for angio‐ genesis events occur, determining further course and outcome of pregnancy. During gestation up to 6 weeks, the primary fetal circulatory system and placental bed with the development of villi are formed, and extensive vascularization of placental villous tree occurs. The 6–8th weeks of pregnancy are marked by the start of transition to the placental circulation, as well as by the most expressed invasion of extravillous trophoblast into maternal spiral arteries (first wave of trophoblast invasion). The period of 11–13 weeks is considered to be borderline and is characterized by the completion of embryogenesis, the starting period of fetal develop‐ ment, fading of the first wave of trophoblast invasion and further increase in the volume of uteroplacental blood flow [4–8].

During trophoblast invasion into endometrium, interactions with components of the extracel‐ lular matrix, which is mediated by cell adhesion molecules, occur. Proteinases participate in the degradation of extracellular matrix and cell migration deep into the myometrium through the uterine spiral arteries. Cytotrophoblast cells change their phenotype from epithelial to endothelial, producing a large number of soluble factors contributing to the development of the vasculature [9, 10].

Growth factors play the key role in vessels formation. They serve as cell mitogens, as attrac‐ tants in the formation of vascular architectonics, and most important, as morphogens. The main regulators of angiogenesis are members of the family of vascular endothelial growth factor (VEGF). In addition to direct activators of angiogenesis, there is a large group of factors, whose effect on angiogenesis is nonspecific. It includes matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) [11–14].

Decidual NK‐cells in early pregnancy, at the stage preceding the invasion of trophoblast into the maternal arteries, produce VEGF, placental growth factor (PLGF) and matrix metallopro‐ teinases (MMPs), in particular MMP‐2 and MMP‐9 [15–17]. These MMPs are collagenases of IV type which specifically hydrolyze the collagen of basement membranes and thereby facilitate cell invasion through the basement membranes and stimulate angiogenesis [18–21]. Decidual NK‐cells are the main source of MMP‐2 and TIMP‐2 from the group of tissue inhibi‐ tors of matrix metalloproteinases (TIMPs) [22–24].

Trophoblast also produces factors regulating processes of vessels formation. Particularly, MMP‐9, TIMP‐1, TIMP‐2 and TIMP‐3 are produced by the cells of extravillous tropho‐ blast. Villous cytotrophoblast cells and invasive endovascular trophoblast produce MMP‐2 which is considered a key regulator of cell invasion in early gestation (up to 8 weeks), according to some authors [17, 19].

Production of anti‐angiogenic factors is an integral part of the normal angiogenesis. As a result of the molecular dialog during vascularization, production of inhibitors serves as a hamper for excessive trophoblast invasion, as well as an obstacle for the further development of the vascular bed and for vascularization of pathologically changed tissue sites. Angiogenic factors are specifically expressed in endothelium and in the placenta during pregnancy. These include receptors VEGF‐R1 (Flt‐1), VEGF‐R2 (Flk‐1, KDR) and VEGF‐R3 (Flt‐4). Soluble forms of these receptors are able to bind growth factors in circulation, slowing or blocking angio‐ genesis [25].

Humoral factors involved in vascular formation processes are more accessible for research in maternal circulation, and change of their content in mother's blood reflects changes in the con‐ tent of these factors in the fetal blood circulation and tissues. In this regard, a complex study of angiogenesis‐related factors and their ratios is crucial for understanding and predicting vascular morphogenesis disorders during pregnancy.
