Microvascular mechanisms of growth restriction after environmental toxicant exposure

摘要 子宫循环和胎盘是专门设计来调节血液的流动和运输， 对胎儿的重要营养妊娠期间母体血流动力学调节的中断可 影响胎儿健康，导致流产和宫内生长受限（IUGR）。当前治疗方案- 对IUGR患者的治疗非常有限，主要集中在早期分娩;因此， 有早产并发症风险的儿童。流行病学研究表明， 暴露于细颗粒物（PM）的妇女具有更高的胎儿丢失和IUGR发展的风险。 我们已经在实验室啮齿动物模型中重现了这种现象，其中动物暴露于纳米尺寸的 二氧化钛（纳米TiO2）气溶胶发展IUGR和遭受更多的"流产"（胎儿 拒绝）。我们已经证明，急性和慢性暴露显著损害子宫血管， 内皮依赖性扩张，严重限制母胎血流并影响胎儿生长。一个 了解子宫和胎盘血流失调的潜在机制对于 开发治疗方法和减少IUGR。根据以前的研究结果，我们假设， 在怀孕期间吸入纳米二氧化钛气溶胶通过干扰胎儿生长促进IUGR的发展 内皮依赖性NO和AA信号级联，导致子宫血管舒张减少， 血流此外，叶酸（FA）补充剂将挽救这种子宫胎盘血流动力学 通过NO信号传导作用来平衡和防止IUGR。使用新的方法和手段， 这些研究将：（1）评估子宫一氧化氮驱动的血管舒张，（2）确定子宫内膜的改变是否与子宫内膜的收缩有关。 花生四烯酸代谢损害子宫血管反应性并影响胎盘灌注，以及（3）评估 补充叶酸对改善子宫胎盘血流量和减轻子宫内膜异位症的治疗作用 母体暴露于纳米TiO2气溶胶后IUGR的发展。这些研究在概念上 创新，因为我们将利用我们独特的资源来确定子宫胎盘中的机制靶点， 对IUGR进行循环和试验指导的营养干预。这项工作是技术创新，因为我们将 使用为评价母胎医学中的环境毒性而开发的新方法。 总的来说，这些研究的成功完成将：（1）建立概念框架，以确定 环境暴露作为IUGR发展的危险因素;（2）揭示了对IUGR发展的新的机制见解。 纳米材料暴露导致的血管发病机制;（3）提供分子基础，以确定如何 纳米材料暴露表现为血管破坏;和（4）确定治疗的机制靶点 改善微血管功能障碍和改善子宫胎盘血流的策略。这些干预- 所有的战略不仅限于PM，但广泛适用于理解的作用， 环境毒物在IUGR病理生理发展中的作用。

ABSTRACT The uterine circulation and placenta are specifically designed to regulate the flow of blood and transport of es- sential nutrients to the fetus. Disruption of maternal hemodynamic regulation during pregnancy can adversely impact fetal health, resulting in miscarriage and intrauterine growth restriction (IUGR). Current treatment op- tions for IUGR patients are extremely limited, focusing primarily on early delivery; thus, putting the mother and child at risk for complications associated with preterm birth. Epidemiological studies indicate that pregnant women exposed to fine particulate matter (PM) have a heightened risk of fetal loss and development of IUGR. We have reproduced this phenomenon in laboratory rodent models, wherein animals exposed to nanosized titanium dioxide (nano-TiO2) aerosols develop IUGR and suffer a greater number of ‘miscarriages’ (fetal reabsorptions). We have demonstrated that acute and chronic exposures significantly impair uterine vascular endothelium-dependent dilation, severely limiting maternal-to-fetal blood flow and impacting fetal growth. An understanding of the mechanisms underlying dysregulation in uterine and placental blood flow is critical for developing treatments and reducing IUGR. Based on previous findings, we hypothesize that maternal inhalation of nano-TiO2 aerosols during pregnancy promotes the development of IUGR by disrupting endothelium-dependent NO and AA signaling cascades, resulting in reduced uterine vasodilation and blood flow. Moreover, folic acid (FA) supplementation will rescue this utero-placental hemodynamic imbalance and prevent IUGR through its action in NO signaling. Using novel approaches and methodolo- gies, these studies will: (1) evaluate uterine nitric oxide-driven vasodilation, (2) determine whether alterations in arachidonic acid metabolism impair uterine vascular reactivity and impact placental perfusion, and (3) assess the therapeutic benefit of dietary folic acid supplementation to improve utero-placental blood flow and attenuate the development of IUGR after maternal exposure to nano-TiO2 aerosols. These studies are conceptually innovative as we will utilize our unique resources to identify mechanistic targets within the utero-placental mi- crocirculation and test directed nutritional interventions for IUGR. This work is technically innovative as we will use novel methodologies developed for the evaluation of environmental toxicity in maternal-fetal medicine. Overall, the successful completion of these studies will: (1) create the conceptual framework to identify environmental exposure as a risk factor for the development of IUGR; (2) reveal new mechanistic insight into the vascular pathogenesis resulting from nanomaterial exposure; (3) provide a molecular basis to identify how nanomaterial exposure manifests as vascular disruptions; and (4) identify mechanistic targets for therapeutic strategies to ameliorate microvascular dysfunction and improve utero-placental blood flow. These intervention- al strategies are not only limited to PM, but are widely applicable to understanding the role of a spectrum of environmental toxicants in the pathophysiological development of IUGR.