Microvascular mechanisms of growth restriction after environmental toxicant exposure

摘要 子宫循环和胎盘是专门用来调节血液流动和ES的运输的。 对胎儿有益的营养物质。妊娠期母体血流动力学调节的紊乱可能会对 影响胎儿健康，导致流产和胎儿宫内生长受限。目前的治疗方案- 对IUGR患者的治疗极其有限，主要集中在早产；因此，将母亲和 有早产并发症风险的儿童。流行病学研究表明，怀孕 暴露在细颗粒物(PM)中的妇女有更高的胎儿损失和IUGR的风险。 我们已经在实验室的啮齿动物模型中重现了这种现象，在这些模型中，动物暴露在纳米级的 二氧化钛(纳米二氧化钛)气雾剂会导致胎儿宫内发育迟缓并遭受更多的流产(胎儿 重吸收)。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，严重限制母体与胎儿之间的血流，影响胎儿生长。一个 了解子宫和胎盘血流失调的机制对于 开发治疗方法，减少宫内发育迟缓。根据之前的发现，我们假设母体 孕期吸入纳米二氧化钛气雾剂对胎儿宫内发育的影响 内皮依赖的NO和AA信号级联，导致子宫血管扩张和 血液流动。此外，补充叶酸(FA)将挽救子宫-胎盘的血流动力学 通过其在NO信号中的作用来平衡和预防IUGR。使用新的途径和方法-- 这些研究将：(1)评估一氧化氮驱动的子宫血管扩张，(2)确定子宫动脉的改变 花生四烯酸代谢损害子宫血管反应性并影响胎盘血流，以及(3)评估 膳食补充叶酸改善子宫胎盘血流量和减薄的疗效观察 孕妇暴露于纳米二氧化钛气雾剂后胎儿宫内发育迟缓的发生。这些研究是概念性的 创新，因为我们将利用我们独特的资源来确定子宫-胎盘未命中的机械性靶点- 针对IUGR的循环和试验指导的营养干预。这项工作在技术上是创新的，我们将 使用开发的新方法评估母婴医学的环境毒性。 总体而言，成功完成这些研究将：(1)建立概念框架，以确定 环境暴露是宫内发育迟缓发生的危险因素；(2)揭示了对 纳米材料暴露引起的血管发病机制；(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；以及(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。这些干预措施- AL策略不仅限于PM，而且广泛适用于理解一系列 环境毒物在IUGR病理生理发育中的作用

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.