Two distinct processes give rise to blood vessels: vasculogenesis and angiogenesis (3). There are three stages in placental vasculogenesis and angiogenesis during villous maturation (Figure 6.1) [50,51].

Figure 6.1

Proposed three steps of vasculogenesis and angiogenesis of placental villous development. The figure is modified based on references 50 and 51. ICM: inner cell mass.

1. Step-1: Vasculogenesis starts with haemangiogenic stem-cell-induced cytotrophoblast differentiation that is regulated by VEGF in a paracrine manner.
2. Step-2: Angiogenesis I (activation) is a prevascular network formation process. Growth factors produced by cytotrophoblast cells and Hofbauer cells play a major role.
3. Step-3: Angiogenesis II (remodeling) is a process of differentiation of perivascular cells (pericytes and myofibroblast-like cells) to form contractile vessels [50,51].

Vasculogenesis: Vasculogenesis refers to the process that begins with the angioblasts: these cells, considered as endothelial cells, first form a primitive vascular network (2). The process of vasculogenesis is divided into three steps: (1) induction of haemangioblasts and angioblasts through fibroblast growth factor; (2) assembly of primordial vessels mediated by vascular endothelial growth factor; and (3) activation of corresponding receptors (FGF and VEGF) to induce the transition from vasculogenesis to angiogenesis (4).

In placenta, de novo formation of blood vessels starts with mesodermally derived precursor cells. Placental vasculogenesis takes place during the development of first villous vessels approximately from day 18 to day 35 p.c. and during the formation of mesenchymal villi from immature intermediate villi. During vasculogenesis, formation of the earliest primitive capillaries is achieved by in situ differentiation of hemangiogenic stem cells that are derived from pluripotent mesenchymal cells. Hemangiogenic stem cells further differentiate to hemangioblastic stem cells that give rise to angioblast cells (the progenitors of endothelial cells) and to hemangioblastic cells (the progenitors of hematopoietic cells) [52,53]. The earliest endothelial tubes are formed between day 21 and day 32 p.c. [14]. Fetal vascularization of the human placenta is the result of local de novo formation of capillaries from mesenchymal precursor cells in the placental villi, rather than protrusion of embryonic vessels into the placenta [50].

Angiogenesis is a physiological process involving the growth of new blood vessels from preexisting vessels. Placental vascular growth begins as early as 21 days p.c. and continues throughout gestation. When the primary villi are formed, the cytotrophoblast core is covered by a thick layer of syncytiotrophoblasts. With the development of secondary villi, a core of irregularly dispersed, homogenous connective tissue cells can be recognized beneath the cytotrophoblast layer. At 6 weeks of gestation, a basal lamina can be detected around the villous vessels. The development of villous capillaries from hemangioblastic cells can be observed until 10–12 weeks of gestation. From 12 weeks onwards, the capillaries coil, bulge, form sinusoids, and protrude towards the trophoblastic layers, forming a so-called syncytiocapillary membrane. Although reliable signs of formation of new vessels are absent in the second half of pregnancy, some capillary sprouts can be seen.

Around 32 days p.c., villous endothelial tubes start to contact each other and the fetal allantoic vessels in the presumptive umbilical cord. A primitive fetoplacental circulation is established. From this day onward, vasculogenic de novo formation of capillaries followed by angiogenesis of expansion of the villous vascular system takes place until term. The angiogenic processes from day 32 until term can be considered as three periods with overlap [14]:

1. Formation of capillary networks from day 32 to 25 weeks p.c. by prevalence of branching angiogenesis.
2. Regression of peripheral capillary webs and formation of central stem vessels between weeks of 15 to 32 p.c.
3. Formation of terminal capillary loops by prevalence of nonbranching angiogenesis.

Placental vascular network development is a tightly controlled vasculogenic and angiogenic process throughout gestation. During the course of vasculogenesis and angiogenesis, angiogenic factors produced by placental cells (trophoblasts, Hofbauer cells, pericytes, and endothelial cells) play a key role. Figure 6.2 illustrates functions of VEGF, FGF, and angiopoietin associated with vasculogenesis and angiogenesis during placental vascular development.

Figure 6.2

Proposed mechanisms of FGF, VEGF, PLGF, and angiopoietin in vasculogenesis and angiogenesis, and their distribution in villous development and presumed paracine control (red). (This figure is adopted from Benirschke K et al. Pathology of the Human Placenta (more...)