Placentation initiates as an invasive phenomenon in which embryo-derived trophoblastic cells progressively integrate into maternal tissues. In this issue of the Journal two articles by Zhou et al. demonstrate convincingly that in addition to invasion, placentation involves an apparently novel process of epithelial–endothelial transformation (1, 2). The acquisition of an endothelial cell phenotype by cytotrophoblastic cells has important implications for the management of placental abnormalities and to our current understanding of basic vascular biology.

Early during implantation, trophoblastic cells from the outer layer of the blastocyst invade the endometrium by secretion of matrix-degrading proteases, migration, and rapid proliferation. Trophoblastic cells also differentiate into two layers: the cytotrophoblast and the syncytiotrophoblast. During the first 2 wk of development, nutrients are exchanged by diffusion. Shortly thereafter, columns of cytotrophoblastic cells invade the endometrium (decidua) as sharp lytic fingers, which eventually pierce the maternal vascular wall, a process termed “endovascular invasion.” As demonstrated by Zhou et al., cytotrophoblastic cells interdigitate between maternal endothelial cells and acquire endothelial characteristics. These include the expression of PECAM, VE-cadherin, VCAM-1, α4 and αvß3 integrins, and with concomitant loss of previously expressed epithelial markers. This epithelial–endothelial conversion is restricted to those cytotrophoblastic cells that leave the fetal compartment and not with trophoblastic cells that remain in the placental villi. Therefore, the spatial restriction in trophoblastic phenotype is a consequence of distinct microenvironments, which effect changes in gene expression and are presumed to reflect distinct functional abilities.