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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

基本信息

批准号：
10514620
负责人：
Phoebe Stapleton
金额：
$ 59.92万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
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/10514620
关键词：
Acute Aerosols Air Pollution Airborne Particulate Matter Animals Arachidonic Acids Attenuated Biological Availability Blood Vessels Blood flow Cardiovascular Diseases Child Chronic Circulation Clinical Data Development Dietary Intervention Diffusion Dose Eicosanoids Elderly Endothelial Cells Endothelium Environment 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 Left Low Birth Weight Infant Maternal Exposure Maternal-fetal medicine Metabolic Diseases Metabolism Methodology Microvascular Dysfunction Modeling Molecular Mothers Myography Neonatal Mortality Nitric Oxide Nutrient Oxygen Particulate Particulate Matter Pathogenesis Patients Perfusion Pharmacological Treatment Physiology Placenta Placental Circulation Predisposition Pregnancy Pregnant Women Premature Birth Preparation Production Prostaglandins I Qualifying 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 constriction 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 mechanical signal nano nanomaterials nanosized neonatal morbidity novel novel strategies particle patient population pharmacologic pregnant pressure prevent response skills targeted treatment titanium dioxide ultrafine particle vasoconstriction

项目摘要

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.

摘要