High-fat diet-induced maternal pre-pregnancy obesity impairs decidual angiogenesis via an Hnrnpa2b1/mPGES-1/PGE2 axis-dependent disruption of stromal-vascular VEGFA signaling

Maternal pre-pregnancy obesity is a well-established risk factor for a spectrum of adverse pregnancy outcomes, yet the molecular mechanisms through which obesity disrupts the early endometrial microenvironment have remained incompletely understood. Although placental abnormalities in obesity are well-documented, the developmental origins of these defects—particularly the molecular events during embryo implantation and decidualization that establish the foundation for normal placentation—have received limited attention. Here, integrating UK Biobank data with mechanistic studies in experimental models, we demonstrate that high-fat diet-induced pre-pregnancy obesity and high-fat exposure disrupt decidual angiogenesis by impairing stromal–endothelial communication. Specifically, high-fat exposure suppresses Hnrnpa2b1 binding to the mPGES-1 promoter, inhibiting prostaglandin E2 (PGE2) synthesis and subsequent vascular endothelial growth factor A secretion from stromal cells and leading to defective vascularization. Functional rescue experiments, including 3D biomimetic chip co-culture systems and targeted in vivo overexpression, confirm that restoring the Hnrnpa2b1/mPGES-1/PGE2 axis reinstates angiogenic competence and improves pregnancy outcomes. Our findings reveal a previously unrecognized metabolic-transcriptional cascade linking high-fat diet-induced obesity to endometrial vascular fragility and propose new diagnostic and therapeutic strategies for obesity-related reproductive failure.