Common and recurrent dysregulated molecular network of placental hypoxia and associated vasculogenesis and angiogenesis in fetal growth restriction

Fetuses with fetal growth restriction (FGR) and selective FGR (sFGR) face elevated health risks both before and after birth. Although the underlying pathomechanisms remain unclear, placental dysfunction is recognized as a major contributing factor. By integrating untargeted transcriptomic data from FGR/sFGR placentae, this study identified 69 differentially expressed mRNAs (DEmRs) and eight differentially expressed miRNAs (DEmiRs). Functional enrichment analysis demonstrated significant enrichment in the angiogenesis and vasculogenesis pathways, with the hypoxia-related genes <i>HIF1A</i> and <i>VEGFA</i> serving as key nodes in the molecular network. Further validation through RNA sequencing (RNAseq), quantitative real-time PCR (RT-qPCR), and immunohistochemistry demonstrated that the expression of the transcriptional regulator <i>HIF1A</i> and the angiogenic factor <i>VEGFA</i> was upregulated in the placentae of sFGR twins and was significantly associated with clinical severity. Our results indicate that placental hypoxia, vasculogenesis, and angiogenesis via the molecular network of <i>HIF1A</i> and <i>VEGFA</i> may play an important role in the pathomechanisms of FGR and sFGR.