Progesterone receptor membrane component 2 is critical for human placental extravillous trophoblast invasion

Abstract

Proper extravillous trophoblast invasion is essential for normal placentation and pregnancy. However, the molecular mechanisms by which cytotrophoblasts differentiate into extravillous trophoblast are unclear. We discovered that in the first-trimester placenta, progesterone receptor membrane component 2 was highly expressed in syncytiotrophoblast but significantly lower in extravillous trophoblast and cytotrophoblasts, indicating a divergent role for progesterone receptor membrane component 2 in trophoblast functions. We aim to examine the role of progesterone receptor membrane component 2 in extravillous trophoblasts invasion mediated by both intracellular and extracellular signals. Progesterone receptor membrane component 2 knockdown and overexpression cells were established in HTR8/SVneo cells, a first-trimester extravillous trophoblast-derived cell model, by transfection with small-interfering RNA or progesterone receptor membrane component 2 plasmids, respectively. Progesterone receptor membrane component 2 knockdown led to cellular morphological changes , enhanced trophoblast proliferation,invasion, and promoted tube formation. These effects were mediated by the activation of hypoxia-inducible factor 1alpha and an increased expression of vascular endothelial growth factor A. The culture supernatant collected from progesterone receptor membrane component 2 knockdown cells did not significantly affect extravillous trophoblast invasion compared to the controls, indicating that extracellular signaling did not robustly regulate extravillous trophoblast invasion in this study. In conclusion, attenuation of progesterone receptor membrane component 2 plays a role in placentation by promoting cell proliferation, invasion, and angiogenesis in extravillous trophoblasts via activation of hypoxia-inducible factor 1 alpha signaling. We thus identified a new function of progesterone receptor membrane component 2 and provide insights on understanding the mechanisms of trophoblast invasion.

Keywords: HIF1α; PGRMC2; m6A; trophoblast invasion.