Microvascular mechanisms of growth restriction after environmental toxicant exposure

环境毒物暴露后生长受限的微血管机制

• 批准号: 10115907
• 负责人: Phoebe Stapleton
• 金额: $ 67.46万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10115907
• 关键词: Acute; Aerosols; Air Pollution; Airborne Particulate Matter; Animals; Arachidonic Acids; Attenuated; Biological Availability; Blood Circulation; Blood Vessels; Blood flow; Cardiovascular Diseases; Child; Chronic; Clinical; Data; Development; Dietary Intervention; Diffusion; Dose; Eicosanoids; Elderly; Endothelial Cells; Endothelium; Environmental Exposure; Epoprostenol; Equilibrium; Evaluation; Exposure to; Fetal Death; Fetal Development; Fetal Growth; Fetal Growth Retardation; Fetal Malnutrition; Fetal Weight; Fetal health; Fetus; Gases; Generations; Goals; Growth; Impairment; In Vitro; Inhalation; Intervention; Laboratories; Lead; Left; Low Birth Weight Infant; Maternal Exposure; Maternal-fetal medicine; Metabolic Diseases; Metabolism; Methodological Studies; Methodology; Microvascular Dysfunction; Modeling; Molecular; Mothers; Myography; Neonatal Mortality; Nitric Oxide; Nutrient; Oxygen; Particulate; Particulate Matter; Pathogenesis; Patients; Perfusion; Pharmacological Treatment; Pharmacology; Physiology; Placenta; Placental Circulation; Pregnancy; Pregnant Women; Premature Birth; Preparation; Production; Prostaglandins I; Rattus; Regulation; Research; Resources; Risk; Risk Factors; Rodent Model; Role; Severities; Signal Transduction; Spontaneous abortion; Testing; Therapeutic; Therapeutic Intervention; Thromboxane A2; Toxic Environmental Substances; Toxic effect; Toxicant exposure; Treatment Efficacy; Uteroplacental Circulation; Uterus; Vascular Endothelium; Vasodilation; Vasodilator Agents; Work; absorption; arteriole; base; cost; design; dietary; epidemiology study; exhaust; fetal; fetal blood; fetal loss; fetus hypoxia; fine particles; folic acid metabolism; folic acid supplementation; healthy pregnancy; hemodynamics; improved; innovation; insight; intravital microscopy; nano; nanomaterials; nanosized; neonatal morbidity; novel; novel strategies; particle; patient population; pregnant; pressure; prevent; response; targeted treatment; titanium dioxide; ultrafine particle; vasoconstriction

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.

抽象的 子宫循环和斑点是专门设计的，以调节血液的流动和ES-运输 胎儿的感性营养素。怀孕期间孕产妇血流动力学调节的破坏会对 影响胎儿健康，从而导致流产和次氨酸内生长限制（IUGR）。当前的治疗方法 IUGR患者的TIONS极为有限，主要集中在早期分娩上；因此，把母亲和 与早产相关的并发症风险的孩子。流行病学研究表明怀孕 暴露于特定事项（PM）的妇女患胎儿流失和IUGR发育的风险增加。 我们已经在实验室啮齿动物模型中重现了这种现象，其中的动物暴露于纳米化 二氧化钛（纳米-TIO2）气溶胶发展起来，并遭受更多的“流产”（胎儿 重新攻击）。我们已经证明，急性和慢性暴露会严重损害子宫血管 内皮依赖性词典，严重限制了母子到狂热的血流和影响胎儿的生长。一个 了解子宫和占血液流动中基础失调的机制对于 开发治疗和减少IUGR。根据以前的发现，我们假设母体 怀孕期间吸入纳米-TIO2气溶胶可通过破坏促进IUGR的发展 内皮依赖性NO和AA信号传导级联反应，导致子宫血管舒张降低和 血流（量。此外，补充叶酸（FA）将营救这种子宫排除血流动力学 不平衡并防止IUGR通过其行动无信号传导。使用新颖的方法和方法 这些研究将：（1）评估子宫一氧化氮驱动的血管舒张，（2）确定是否改变 花生四烯酸代谢会损害子宫血管反应性和影响斑点灌注，以及（3）评估 补充饮食叶酸的治疗益处可改善子宫斑血液流量并减轻 孕产妇接触纳米-TIO2气溶胶后，IUGR的发展。这些研究在概念上是 创新性，因为我们将利用我们的独特资源来确定子宫阵地中的机械目标 IUGR的串联和测试定向营养干预措施。这项工作在技术上是创新的 使用用于评估母体狂热医学环境毒性的新方法。 总体而言，这些研究的成功完成将：（1）创建概念框架以识别 环境暴露是IUGR发展的危险因素； （2）揭示新的机械洞察力 纳米材料暴露引起的血管发病机理； （3）提供了分子基础，以确定 纳米材料暴露表现为血管干扰； （4）确定治疗的机理目标 改善微血管功能障碍并改善子宫斑血液流动的策略。这些干预 - AL策略不仅限于PM，而且广泛适用于了解一系列频谱的作用 IUGR病理生理发展中的环境有毒物质。