The placental phenotype of Esx1 mutant mice indicates that trophoblast cells are critically involved in the vascularization of the labyrinth, suggesting a paracrine pathway for regulating placental vascular Ibrutinib cell line formation and morphogenesis possible by transcriptional signals of Esx1 from the trophoblast cells [118], although the
downstream targets of Esx1 are currently unknown. As a primary active site of angiogenesis, the placenta is one of the richest sources of both pro-angiogenic and anti-angiogenic factors. During the third trimester of both ovine and human pregnancy, at a time when maternal–fetal interface vascular growth, blood flow, and fetal weight increase exponentially, the fetal and maternal compartments of the placentas produce numerous angiogenic factors, including VEGF [107, 71, 60], FGF2 [47], PlGF [80], endocrine gland-derived-VEGF [70], TGF-β1 [29], leptin [125], angiopoietins [104], and Slit/Robo signaling cues [77]. It is noteworthy that this list is still expanding. It is also becoming clear that the placenta also produces a large number of anti-angiogenic factors, that is, soluble VEGFR1 (sFlt1) NVP-BKM120 in vivo and soluble TGF-β1 receptor endoglin [72]. These factors are important for the fine tuning of placental angiogenesis, preventing it from overgrowth. VEGF is the first angiogenic factor identified [107]. Among
many growth factors surveyed, VEGF is the only one that is expressed almost ubiquitously at sites of angiogenesis and its expression correlates most closely with the spatial and temporal events of vascular growth. Following the discovery of a family of structurally related growth factors, for
example, VEGF-B, -C, -D, and -E as well as PIGF [56, 33, 95], the conventional form has been renamed as VEGFA or simply VEGF. VEGF consists of at least seven structurally homologous isoforms (VEGF121, VEGF145, VEGF148, VEGF165, VEGF183, VEGF189, and VEGF206), with a potent mitogenic activity for endothelial cells Org 27569 [101]. These isoforms are produced from different splicing variants of VEGF pre-mRNA, differing from each other with the presence or absence of sequences encoded by exons 6 and 7 [111]. The majority of VEGF-producing cells preferentially express VEGF121, VEGF165, and VEGF189, whereas the others are comparatively rare. During normal pregnancy, human placental VEGF expression increases with gestational age. The fetal cotyledon and maternal caruncle as well as placenta amnion and chorion produce large amounts of VEGF during the third trimester of ovine [21, 128, 9] and human [23] pregnancy. In addition, fetal placental endothelial cells also express VEGF [112]. We have found that akin to most arterial endothelial cells, placental artery endothelial cells express the high affinity VEGF receptor VEGFR1 (also called fms-related tyrosine kinase 1/Flt1) and VEGFR2 (also called kinase insert domain receptor/KDR) as well as the VEGF co-receptors neuropinin-1 and -2 [112].