Human placental villous stromal extracellular matrix regulates fetoplacental angiogenesis in severe fetal growth restriction

Abstract

Pregnancies complicated by severe, early-onset fetal growth restriction with abnormal Doppler velocimetry (FGRadv) have a sparse villous vascular tree secondary to impaired angiogenesis. As endothelial cell (EC) and stromal matrix interactions are key regulators of angiogenesis, we investigated the role of placental stromal villous matrix on fetoplacental EC angiogenesis. We have developed a novel model of generating placental fibroblast (FB) cell-derived matrices (CDMs), allowing us to interrogate placenta-specific human EC and stromal matrix interactions and their effects on fetoplacental angiogenesis. We found that as compared with control ECs plated on control matrix, FGRadv ECs plated on FGRadv matrix exhibited severe migrational defects, as measured by velocity, directionality, accumulated distance, and Euclidean distance in conjunction with less proliferation. However, control ECs, when interacting with FGRadv CDM, also demonstrated significant impairment in proliferation and migratory properties. Conversely several angiogenic attributes were rescued in FGRadv ECs subjected to control matrix, demonstrating the importance of placental villous stromal matrix and EC-stromal matrix interactions in regulation of fetoplacental angiogenesis.

Placental DNA methylation analysis of selective fetal growth restriction in monochorionic twins reveals aberrant methylated CYP11A1 gene for fetal growth restriction

“…And the placental vascular development can significantly impact placental function, subsequently leading to fetal growth restriction. In cases of severe fetal growth restriction, it has been observed that matrices derived from placental stromal cells impaired fetoplacental angiogenesis 32 . Placental mesenchymal stromal cells (pMSCs) of FGR have the potential to negatively impact vascular function, as demonstrated by significant alterations in FBLN2 and HAS2 genes in pMSCs, which are associated with vascular function 33,34 .…”

“…In cases of severe fetal growth restriction, it has been observed that matrices derived from placental stromal cells impaired fetoplacental angiogenesis. 32 Placental mesenchymal stromal cells (pMSCs) of FGR have the potential to negatively impact vascular function, as demonstrated by significant alterations in FBLN2 and HAS2 genes in pMSCs, which are associated with vascular function. 33,34 These findings highlight the importance of intercellular placental stromal cells and endothelial cells, which is crucial for placental angiogenesis.…”

Flow in fetoplacental-like microvessels in vitro enhances perfusion, barrier function, and matrix stability

“…Low expression of these EVM proteins, observed in the absence of flow, could explain their increased destabilization over time. A recent study reported that endothelial cells plated on matrices derived from villous stromal fibroblasts where fetal growth restriction was clinically observed (reduced expression of collagen I and fibronectin) exhibited impaired proliferation and migration, suggesting that matrix composition is crucial for fetoplacental vascular development ( 67 ).…”

Bioinformatics Analysis Identifies Potential Related Genes in the Pathogenesis of Intrauterine Fetal Growth Retardation

“…ECM might regulate the angiogenesis of placenta to influence fetal development. [24][25][26] The second one is PID NFAT tfpathway, which is calcineurin-regulated NFAT-dependent transcription in lymphocytes. Five proteins (NFAT1-5) make up the NFAT transcription factor family.…”