Retinoic Acid Regulates Fetoplacental Vascularization via Notch Signaling and a SEMA3E/F-PLEXIND1 Axis 79 views

The placenta is essential for fetal growth and survival yet remains one of the most understudied organs. Impaired placental vascularization is the most common placental pathology, contributing to early pregnancy loss, intrauterine growth restriction (IUGR), and pre-eclampsia, a leading cause of maternal mortality. A growing body of evidence links Vitamin A deficiency (VAD) to these vascular defects. While VAD is considered rare in developed countries, recent studies revealed shockingly high prevalence among pregnant women in the United States, underscoring its clinical importance. The biologically active metabolite of Vitamin A, retinoic acid (RA), regulates endothelial cell (EC) cycle progression through induction of p21 and p27, promoting G1 arrest that enables arterial-venous specification. In the absence of RA, ECs undergo unchecked proliferation, leading to vascular defects, as observed in Raldh2-deficient embryos and in placental models lacking key cell cycle regulators. These findings suggest that RA plays a fundamental role in fetoplacental vascularization, yet the underlying mechanisms remain undefined. The fetoplacental vasculature is uniquely characterized by reciprocal endothelial–trophoblast interactions and an inverted oxygen gradient between arteries and veins, raising the possibility that distinct regulatory mechanisms govern endothelial fate in this system. Our work identifies how Vitamin A and its downstream effectors Notch and SEMA3E/PLEXIND1 signaling regulate EC cycle states and arterial-venous specification in the developing fetoplacental vasculature. Understanding these pathways will provide critical insights into the developmental origins of placental vascular pathologies and inform new strategies to prevent pregnancy complications linked to VAD and beyond.

PHD (Doctor of Philosophy)

2026-05-16