HUMAN CYTOTROPHOBLASTS ADOPT A VASCULAR PHENOTYPE AS THEY DIFFERENTIATE - A STRATEGY FOR SUCCESSFUL ENDOVASCULAR INVASION

Establishment of the human placenta requires that fetal cytotrophoblas t stem cells in anchoring chorionic villi become invasive. These cytot rophoblasts aggregate into cell columns and invade both the uterine in terstitium and vasculature, anchoring the fetus to the mother and esta blishing blood flow to the placenta. Cytotrophoblasts colonizing spira l arterioles replace maternal endothelium as far as the first third of the myometrium. We show here that differentiating cytotrophoblasts tr ansform their adhesion receptor phenotype so as to resemble the endoth elial cells they replace. Cytotrophoblasts in cell columns show reduce d E-cadherin staining and express VE-(endothelial) cadherin, platelet- endothelial adhesion molecule-1, vascular endothelial adhesion molecul e-1, and alpha 4-integrins. Cytotrophoblasts in the uterine interstiti um and maternal vasculature continue to express these receptors, and, like endothelial cells during angiogenesis, also stain for alpha V bet a 3. In functional studies, alpha V beta 3 and VE-cadherin enhance, wh ile E-cadherin restrains, cytotrophoblast invasiveness. Cytotrophoblas ts ex-pressing alpha 4 integrins bound immobilized VCAM-1 in vitro, su ggesting that this receptor-pair could mediate cytotrophoblast-endothe lium or cytotrophoblast-cytotrophoblast interactions in vivo, during e ndovascular invasion. In the pregnancy disorder preeclampsia, in which endovascular invasion remains superficial, cytotrophoblasts fail to e xpress most of these endothelial markers (Zhou et al., 1997. J. Clin. Invest. 99:2152-2164.), suggesting that this adhesion phenotype switch is required for successful endovascular invasion and normal placentat ion.