Molecular Regulators of CTB Pseudovasculogenesis

Our laboratory studies molecular aspects of the CTB differentiation pathway that leads to uterine invasion. Given the cells' unusual ability to line the uterine blood vessels and channel maternal blood, we hypothesized that they might replicate portions of standard vasculogenesis and/or angiogenesis programs. As a first test of this theory we examined the cells' expression of adhesion molecules during interstitial and endovascular invasion. We found that the onset of CTB differentiation/invasion is characterized by reduced staining for receptors characteristic of polarized CTB epithelial-type progenitors—integrin a6b4 and E-cadherin—and the onset of expression of adhesion receptors characteristic of endothelium—VE-cadherin, IgG family members VCAM-1 and PECAM-1, and integrins aVb3 and aipi. Accordingly, we termed this phenomenon pseudovasculogenesis (reviewed in Ref. [3]). Thus, as CTBs from anchoring villi invade and remodel the wall of the uterus, these epithelial cells of ectodermal origin acquire an adhesion receptor repertoire characteristic of endothelial cells. We theorize that this switch permits the heterotypic adhesive interactions that allow fetal and maternal cells to cohabit the uterine vasculature during normal pregnancy.

These findings prompted us to examine the CTB repertoire of ligands and receptors that control blood and/or lymphatic development [4]. These studies used a combination of in situ and in vitro analyses to characterize the cells' expression of vascular endothelial growth factor (VEGF) family members. CTB differentiation/invasion during the first and second trimesters of pregnancy was associated with down-regulation of VEGF receptor (VEGFR)-2. Invasive CTBs in early gestation expressed VEGF-A, VEGF-C, placental growth factor (PlGF), VEGFR-1, and VEGFR-3 and, at term, VEGF-A, PlGF, and VEGFR-1. In vitro the cells incorporated VEGF-A into the surrounding extracellular matrix; PlGF was secreted. Experiments directed toward understanding the functions of these ligand-receptor pairs showed that CTBs respond to the VEGF ligands they produce. Blocking ligand binding significantly decreased their expression of integrin a1, an adhesion molecule highly expressed by endovascular CTBs, and increased apoptosis. Together, the results of this study showed that VEGF family members are autocrine regulators of CTB pseudovasculoge-nesis and survival.

In addition, we examined the cells' expression of angiopoietin (Ang) ligands and their Tie receptors [5]. At the mRNA and protein levels, CTBs predominantly expressed Ang2. The absence of receptor expression suggested that Ang2, along with CTB-derived VEGF family ligands, could have paracrine effects on the maternal vasculature. This theory was tested by culturing uterine microvas-cular endothelial cells in CTB-conditioned medium, which supported their growth. Removal of VEGF-C, PlGF, and/or Ang2 from the medium caused a marked reduction in cell number as a result of massive apoptosis. We also assayed the angiogenic potential of CTB-derived factors in the chick chorioallantoic membrane assay (Figure 2). The cell-conditioned medium stimulated angiogenesis to a level comparable to that of basic fibroblast growth factor (FGF). Removal of VEGF-C, PlGF, and/or Ang2 from the medium reduced this activity by 70 to 80 percent. These data suggest that invasive human CTBs use an unusual repertoire of factors to influence the angiogenic state of maternal blood vessels and that this cross talk plays an important part in the endovascular component of uterine invasion.

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