Overexpression of the aryl hydrocarbon receptor nuclear translocator partially rescues fetoplacental angiogenesis in severe fetal growth restriction

Abstract

Abstract Pregnancies complicated by severe fetal growth restriction with abnormal umbilical artery Doppler velocimetry (FGRadv) are at substantial risk for adverse perinatal and long-term outcomes. Impaired angiogenesis of the placental vasculature in these pregnancies results in a sparse, poorly branched vascular tree, which structurally contributes to the abnormally elevated fetoplacental vascular resistance that is clinically manifested by absent or reversed umbilical artery Doppler indices. Previous studies have shown that aryl hydrocarbon receptor nuclear translocator (ARNT) is a key mediator of proper placental angiogenesis, and within placental endothelial cells (ECs) from human FGRadv pregnancies, low expression of ARNT leads to decreased vascular endothelial growth factor A (VEGFA) expression and deficient tube formation. Thus, the aim of the present study was to determine the effect of VEGFA administration or ARNT overexpression on angiogenic potential of FGRadv ECs. ECs were isolated and cultured from FGRadv or gestational age-matched control placentas and subjected to either vehicle vs VEGFA treatment or transduction with adenoviral-CMV (ad-CMV) vs adenoviral-ARNT (ad-ARNT) constructs. They were then assessed via wound scratch and tube formation assays. We found that VEGFA administration nominally improved FGRadv EC migration (P<0.01) and tube formation (P<0.05). ARNT overexpression led to significantly enhanced ARNT expression in FGRadv ECs (P<0.01), to a level similar to control ECs. Despite this, FGRadv EC migration (P<0.05) and tube formation (P<0.05) were still only partially rescued. This suggests that although ARNT does play a role in fetoplacental EC migration, other factors in addition to ARNT are likely also important in placental angiogenesis.