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

## TL;DR

Retinoic acid helps form proper blood vessels in the placenta by controlling cell growth and signaling pathways.

## Contribution

This study identifies a new mechanism by which retinoic acid regulates placental vascularization through Notch and SEMA3E/F-PLEXIND1 signaling.

## Key findings

- RA deficiency causes placental endothelial hyperproliferation and impaired vascular remodeling.
- RA regulates endothelial growth and vascular remodeling via Notch signaling.
- RA controls endothelial guidance through a SEMA3E/F-PLEXIND1 signaling axis.

## Abstract

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.

•Retinoic acid (RA) deficiency disrupts fetoplacental vascular remodeling•RA limits endothelial proliferation via Notch-mediated cell-cycle control•RA regulates endothelial guidance via SEMA3–PLEXIND1 signaling•Maternal ATRA supplementation rescues placental vascular defects

Retinoic acid (RA) deficiency disrupts fetoplacental vascular remodeling

RA limits endothelial proliferation via Notch-mediated cell-cycle control

RA regulates endothelial guidance via SEMA3–PLEXIND1 signaling

Maternal ATRA supplementation rescues placental vascular defects

Molecular biology; Cell biology; Developmental biology