Unraveling the Matrix: Proteomic Profiling Reveals Stromal ECM Dysregulation in Severe Early-Onset Fetal Growth Restriction

An underdeveloped placental vasculature is a cardinal feature in severe, early-onset fetal growth restriction with absent/reversed umbilical artery Doppler end-diastolic velocities (FGRa/r). Tissue microenvironment is a key mediator of angiogenesis; yet, the role of placental villous stromal extracellular matrix (ECM) in FGRa/r remains unknown. We applied an ECM-optimized, proteomic workflow to villous tissue and placental fibroblast cell-derived matrices (CDM) from FGRa/r, gestational age-matched controls, and uncomplicated term pregnancies. No significant differences were detected in villous tissue, although there was a trend toward increased type I collagen and fibronectin in FGRa/r placentas. FGRa/r CDM, however, appeared distinct from both control groups, with elevated matrisome abundance, greater insolubility of matrisome-associated proteins, and 44 differentially expressed matrisome proteins. Fibronectin emerged as a central network hub among differential matrisome proteins, interacting with thrombospondin-1, vitronectin, and transglutaminase-2, all of which were enriched in FGRa/r CDM, suggesting excessive deposition and crosslinking. In contrast, regulators of ECM remodeling and TGFβ activity, including fibrillin-1, decorin, and syndecan-4, were depleted. These features suggest a pro-fibrotic, dysregulated stroma with diminished remodeling capacity. Our findings establish the first, comprehensive proteomic map of human placental stromal matrisome and provide a molecular framework for understanding how aberrant ECM organization contributes to placental dysfunction.