Retinoic acid regulates fetoplacental vascularization via notch signaling and a SEMA3E/F-PLEXIND1 axis

The placenta is vital for fetal development, and altered placental vascularization, the most common placental pathology, underlies prevalent disorders, including fetal growth restriction, prematurity, and pregnancy complications. Impaired placental vascularization is associated with Vitamin A deficiency, but the mechanisms are undefined. To investigate this, we used retinoic acid (RA)-deficient Raldh2^-/- embryos, and found they exhibit allantoic and placental endothelial hyperproliferation and impaired arterial-venous remodeling, which were rescued by providing all-trans-RA (ATRA) via maternal diet. Single-cell RNA sequencing of E9.5 Raldh2 ^+/+ , Raldh2^-/-, and Raldh2^-/- + ATRA placental cells, and functional assays, revealed that RA regulates endothelial growth and vascular remodeling via Notch signaling. We also uncovered a PLEXIND1-SEMA3E/F signaling axis between fetal endothelial cells and chorionic trophoblast precursors that is impaired with RA deficiency and rescued with ATRA. Our data suggest that RA-mediated signaling regulates allantois and placental endothelial cell growth, specification, and guidance required for chorioallantoic fusion and fetoplacental vascularization.