Dichotomous effects of aryl hydrocarbon receptor (AHR) activation on human fetoplacental endothelial cell function.

introductionMaternal cigarette smoking is associated with elevated fetoplacental vascular resistance and fetal growth restriction (FGR). While studies have demonstrated varying effects of nicotine on blood flow, the role of polycyclic aromatic hydrocarbons (PAHs), abundant toxins in cigarette smoke that cross the placenta, has not been elucidated. We hypothesized that exposure of human fetoplacental endothelial cells (ECs) to the PAH benzo[a]yrene (BaP) would result in up-regulation of cyclooxygenase-2 (PTGS2) and preferential production of vasoconstrictive prostanoids via activation of the aryl hydrocarbon receptor (AHR) pathway.

methodsECs were isolated, cultured, and treated with vehicle or BaP. ECs were subjected to real-time PCR, western blotting, enzyme immunoassays, wound scratch assays, tube formation assays, and RNA interference against AHR. Statistical analyses were performed with Student's t-test, one-way ANOVA followed by multiple comparisons testing when appropriate, or the Kruskal-Wallis H test.

resultsBaP induced PTGS2 expression (p < 0.05) and production of the stable metabolite of prostacyclin (p = 0.001) in fetoplacental ECs without affecting thromboxane. These effects were ablated by PTGS2 inhibition (p < 0.01) and RNA interference of AHR (p < 0.001). Surprisingly, despite the induction of prostacyclin, EC migration (p = 0.007) and tube formation (p = 0.003) were inhibited by BaP. AHR inhibition, however, rescued tube formation (p = 0.008). DISCUSSION: BaP-mediated AHR activation results in induction of PTGS2 expression and enhanced production of prostacyclin metabolite. Despite an increase in this vasodilatory and pro-angiogenic prostanoid, BaP exposure also impairs EC migration and angiogenesis through AHR. This suggests that PAH may adversely affect the fetoplacental vasculature through its regulation of angiogenesis.