Dichotomous effects of aryl hydrocarbon receptor (AHR) activation on human fetoplacental endothelial cell function.
Dichotomous effects of aryl hydrocarbon receptor (AHR) activation on human fetoplacental endothelial cell function.
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DOI：
10.1016/j.placenta.2016.06.004
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发表时间：
2016-08
期刊：
影响因子：
3.8
通讯作者：
Su EJ
中科院分区：
文献类型：
--
作者：
Palatnik A;Xin H;Su EJ
母亲吸烟与胎儿胎盘血管阻力升高和胎儿生长受限（FGR）有关。虽然研究已经证明尼古丁对血液流动的不同影响，但多环芳烃（PAH）的作用尚未阐明，多环芳烃是香烟烟雾中穿过胎盘的丰富毒素。我们假设，暴露于PAH苯并[a]芘（BaP）的人胎儿胎盘内皮细胞（EC）将导致环氧化酶-2（PTGS-2）的上调，并通过激活芳香烃受体（AHR）途径优先产生血管收缩性前列腺素。分离、培养内皮细胞，并用载体或BaP处理。对内皮细胞进行实时PCR、蛋白质印迹、酶免疫测定、伤口划痕测定、管形成测定和针对AHR的RNA干扰。采用Student t检验、单因素ANOVA，随后进行多重比较检验（如适用）或Kruskal-Wallis H检验进行统计分析。BaP诱导胎儿胎盘EC中PTGS 2表达（p<0.05）和前列环素稳定代谢产物的产生（p=0.001），而不影响血栓素。PTGS 2抑制（p<0.01）和AHR的RNA干扰（p<0.001）消除了这些作用。令人惊讶的是，尽管前列环素的诱导，EC迁移（p=0.007）和管的形成（p=0.003）抑制BaP。然而，AHR抑制挽救了管形成（p=0.008）。BaP介导的AHR激活导致PTGS 2表达的诱导和前列环素代谢产物的增加。尽管这种血管舒张和促血管生成的前列腺素类增加，但BaP暴露也损害EC迁移和通过AHR的血管生成。这表明PAH可能通过调节血管生成对胎儿胎盘血管系统产生不利影响。
Maternal 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. ECs 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. BaP 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). 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.