Unraveling the matrix: Proteomic profiling reveals stromal ECM dysregulation in severe early-onset fetal growth restriction

ABSTRACT: Severe, early-onset fetal growth restriction with absent or reversed end-diastolic umbilical artery velocities (FGRa/r) is marked by profound placental vascular insufficiency, yet the role of the villous stromal extracellular matrix (ECM) in this pathology remains poorly defined. Here, we applied an ECM-optimized proteomic workflow to villous tissue and fibroblast-derived cell matrices (CDMs) from FGRa/r, gestational age–matched preterm controls, and uncomplicated term placentas. While villous tissue exhibited only subtle trends toward increased type I collagen (COL1A1/2) and fibronectin (FN1), CDMs revealed a distinct FGRa/r signature characterized by elevated total matrisome abundance, greater insolubility of matrisome-associated proteins, and 44 differentially expressed insoluble ECM proteins. Fibronectin emerged as a central network hub, interacting with thrombospondin-1 (THBS1), vitronectin (VTN), and transglutaminase-2 (TGM2), 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 (FBN1), decorin (DCN), and syndecan-4 (SDC4), were depleted. These features define a pro-fibrotic, dysregulated stromal microenvironment with diminished remodeling capacity and altered basement membrane composition. Together, our findings establish the first comprehensive proteomic map of the human placental stromal matrisome in FGRa/r, highlight the ECM as a critical regulator of angiogenic competence, and provide a molecular framework for understanding how aberrant ECM organization contributes to placental dysfunction.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Primary Cell, Placenta, Fibroblast

DISEASE(S): Placenta Disease

SUBMITTER: Kirk Hansen  

LAB HEAD: Emily Su

PROVIDER: PXD070632 | Pride | 2025-12-08

REPOSITORIES: Pride