Maternal hyperhomocysteinemia induces fetal growth restriction by suppressing angiogenesis at the maternal-fetal interface.

Maternal hyperhomocysteinemia (HHcy) is closely linked to fetal growth restriction (FGR), yet the underlying mechanisms remain incompletely understood. In this study, we established a rat model of HHcy by administering a high-methionine diet during pregnancy and confirmed the presence of FGR through fetal weight analysis. Histological evaluation of the maternal-fetal interface revealed reduced vascular density in both the decidua and placenta, accompanied by dysregulated expression of key angiogenic factors in decidua. To elucidate the mechanistic basis of these changes, primary decidual stromal cells (DSCs) were isolated and RNA sequencing was performed. HHcy impaired the proangiogenic capacity of DSCs by suppressing vascular endothelial growth factor A (VEGFA) secretion. Transcriptomic profiling identified significant enrichment of lipid metabolism pathways in HHcy-exposed decidua. Further molecular analyses revealed that CD36 played a central role in mediating HHcy-induced lipid metabolic disturbances, which in turn activated the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Importantly, pharmacological inhibition of CD36 in DSCs alleviated lipid accumulation, suppressed PPAR pathway activation, and restored VEGFA expression and secretion, thereby rescuing DSCs-mediated angiogenesis. Collectively, our findings suggest that maternal HHcy upregulates CD36 expression in DSCs, leading to lipid metabolism dysregulation and impaired VEGFA-mediated angiogenesis possibly via the PPAR pathway, ultimately contributing to the pathogenesis of FGR. This is the first study to implicate lipid metabolism as a critical regulator of decidual angiogenesis, offering novel mechanistic insights and a potential therapeutic target for HHcy-associated pregnancy complications.