Human cytotrophoblasts adopt a vascular phenotype as they differentiate. A strategy for successful endovascular invasion?

Abstract

Establishment of the human placenta requires that fetal cytotrophoblast stem cells in anchoring chorionic villi become invasive. These cytotrophoblasts aggregate into cell columns and invade both the uterine interstitium and vasculature, anchoring the fetus to the mother and establishing blood flow to the placenta. Cytotrophoblasts colonizing spiral arterioles replace maternal endothelium as far as the first third of the myometrium. We show here that differentiating cytotrophoblasts transform their adhesion receptor phenotype so as to resemble the endothelial cells they replace. Cytotrophoblasts in cell columns show reduced E-cadherin staining and express VE-(endothelial) cadherin, platelet-endothelial adhesion molecule-1, vascular endothelial adhesion molecule-1, and ␣ 4-integrins. Cytotrophoblasts in the uterine interstitium and maternal vasculature continue to express these receptors, and, like endothelial cells during angiogenesis, also stain for ␣ V ␤ 3. In functional studies, ␣ V ␤ 3 and VE-cadherin enhance, while E-cadherin restrains, cytotrophoblast invasiveness. Cytotrophoblasts expressing ␣ 4 integrins bound immobilized VCAM-1 in vitro, suggesting that this receptor-pair could mediate cytotrophoblast-endothelium or cytotrophoblast-cytotrophoblast interactions in vivo, during endovascular invasion. In the pregnancy disorder preeclampsia, in which endovascular invasion remains superficial, cytotrophoblasts fail to express 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 placentation. ( J. Clin. Invest. 1997.

Epithelial-mesenchymal transition during extravillous trophoblast differentiation

“…In vitro evidence demonstrated that knock-down of E-cadherin significantly increased invasiveness of the EVT cell line JEG-3 56 and of isolated second trimester trophoblast cells. 65 This evidence suggests E-cadherin is important in the maintenance of an epithelial phenotype in trophoblasts, and reduced E-cadherin expression is associated with trophoblasts acquiring a migration and/or invasion potential. In this respect, trophoblast cells behave in a similar manner to other epithelial cell types and cancer cells.…”

“…6 Ecadherin is present in villous cytotrophoblasts and is reduced in the distal regions of the EVT cell columns and in migrating and invading EVT within the decidua in first and second trimester placental tissues. 65 Floridon et al, 66 reported a transient down regulation of E-cadherin expression in migratory and invasive EVT that was restored when trophoblasts aggregated in the decidua to form giant cells, and in the vessel wall after completion of trophoblast migration and invasion. In vitro evidence demonstrated that knock-down of E-cadherin significantly increased invasiveness of the EVT cell line JEG-3 56 and of isolated second trimester trophoblast cells.…”

“…73 VE-cadherin is absent from villous trophoblast but is expressed in the trophoblast cell columns, interstitial EVT and spiral artery endothelial cells (unmodified vessels). 65 VE-cadherin shows an inverse relationship with E-cadherin in trophoblasts, and switching cadherin phenotype from an epithelial to vascular endothelial phenotype may allow trophoblasts to invade and interact with maternal vessels. 65 Subsequently, VEcadherin was shown to facilitate the passage of endovascular trophoblasts across the endothelium.…”

Activation of Mitogen-Activated Protein Kinase Is Required for Migration and Invasion of Placental Site Trophoblastic Tumor

“…Western blot analysis demonstrated that IST-2 cells expressed HLA-G and Mel-CAM but not E-cadherin, an immunohistochemical phenotype consistent with EVT cells in a normal placental site and in PSTT tissues (Figure 2B). [25][26][27][28] …”

Excessive stimulation of poly(ADP‐ribosyl)ation contributes to endothelial dysfunction in pre‐eclampsia

“…Although the precise aetiology of pre-eclampsia is unknown, current thinking suggests it to be a two-step disease process. In this model, inappropriate adaptation of the interface between the maternal vasculature and the developing placenta leads to inadequate perfusion of the fetoplacental unit (Lunell et al, 1984;Zhou et al, 1997). This stimulates the release of circulating factors that lead to maternal vascular dysfunction (Ashworth et al, 1998).…”