H2S and Uterine Vasodilation in Pregnancy and Preeclampsia

妊娠和先兆子痫中的 H2S 与子宫血管舒张

基本信息

批准号：
10454412
负责人：
DONGBAO CHEN
金额：
$ 41.2万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
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：
2021-07-20 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10454412
关键词：
Anabolism Animal Model Animals Arteries Bathing Biochemical Biopsy Blood Vessels Blood flow Cardiovascular system Clinical Trials Coculture Techniques Coupled Cystathionine Cysteine Data Endothelial Cells Endothelium Enzymes Estrogens Family Fetal Growth Retardation Fetus Functional disorder Genetic Transcription Human Hydrogen Sulfide Hypertension Impairment In Vitro Knowledge Lyase Mediating Mediator of activation protein Methods Modeling Molecular Myography Myometrial Nitric Oxide Nutrient Organ Oxides Oxygen Pharmacology Physiological Play Potassium Channel Pre-Eclampsia Pregnancy Pregnant Women Production Rat-1 Rattus Regulation Reporting Research Role Signal Transduction Smooth Muscle Smooth Muscle Myocytes Symptoms System Testing Therapeutic Therapeutic Intervention Up-Regulation Uterus Vascular Diseases Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factors Vasodilation Vasodilator Agents Woman Work angiogenesis cohesion hemodynamics high risk in vitro Model in vivo in vivo Model infancy multidisciplinary myometrium normotensive novel overexpression pregnancy disorder pregnancy health pregnant pressure prevent tool translational approach ultrasound

项目摘要

PROJECT SUMMARY Once conceived, a woman’s cardiovascular system undergoes dramatic structural and functional changes to accommodate the increasing demands of the fast growing fetus, resulting in profound uterine artery dilation exemplified by dramatic rise in uterine blood flow (UBF). UBF is a rate-limiting factor for pregnancy health because an insufficient rise in UBF during pregnancy is causative for intrauterine growth restriction and preeclampsia (PE) characterized by systemic endothelial damage and vascular dysfunction. Since 1900’s, numerous studies have concluded that local endothelial nitric oxide (NO)-mediated vasodilation is the major mechanism controlling rise in UBF. However, blockade of local NO production only partially inhibits baseline pregnancy-associated rise in UBF, suggesting that other mediator(s) are involved. Endogenous hydrogen sulfide (H2S), mainly synthesized from L-cysteine by two key enzymes: cystathionine -synthase (CBS) and cystathionine -lyase (CSE), is an extremely potent proangiogenic vasodilator. We initially posited that local CBS/H2S production can fill the mechanism behind NO to mediate UA vasodilation during pregnancy. Indeed, we reported that pregnancy dramatically augments UA H2S biosynthesis by selectively upregulating EC and SM CBS but not CSE expression in animals (rats and ewes) and women in vivo and that H2S stimulates pregnancy-dependent dilation of pressurized UA ex vivo. In animal models of PE and women with PE, we found that pregnancy-augmented myometrial UA CBS/H2S is significantly downregulated. However, research on H2S in uterine hemodynamics is still in its infancy; many important key questions need to be answered before a physiological and a pathophysiological role of CBS/H2S signaling in normal pregnancy and PE can be determined. In this new RO1 we propose to test a novel hypothesis that enhanced UA EC and SM CBS/H2S production mediates pregnancy-associated UA dilation by interacting with vascular endothelial growth factor and EC eNOS-NO and downregulated UA CBS/H2S signaling contributes to the vascular dysfunction in PE. We will test this hypothesis by a multidisciplinary translational approach with biochemical, cellular, molecular, physiological, and pharmacological methods coupled with rat models in vivo, freshly isolated human and rat UA rings ex vivo, novel human UA EC (hUAEC) and smooth muscle cell (hUASMC) models in vitro, and myometrial UAs from normotensive vs. PE pregnant women. We have an outstanding team with a track record of long-term productive collaborative research in the field and unique tools needed to complete this exciting and important project. We believe that the novel studies outlined in this RO1 will provide new data to fill a knowledge gap on the physiological and pathophysiological role for H2S in in uterine hemodynamic regulation and this knowledge will provide a compelling rationale for clinical trials to explore the therapeutic potential of H2S in women in high risk of PE.

项目摘要一旦构思，女人的心血管系统就会发生戏剧性的结构和功能性更改适应快速生长的胎儿的需求不断增长，导致子宫动脉词典子宫血流（UBF）的急剧上升为例。 UBF是怀孕健康的限制因素因为怀孕期间UBF的增加不足以用于限制内生长限制和子痫前期（PE）以全身性内皮损伤和血管功能障碍为特征。自1900年代以来许多研究得出的结论是，局部内皮一氧化氮（NO）介导的血管舒张是主要的控制UBF的机制。但是，封锁本地无生产仅部分抑制基线 UBF与妊娠相关的增加，表明涉及其他介体。内源氢硫化物（H2S），主要由两种关键酶从L-半胱氨酸合成：胱淀粉合成酶（CBS）和胱淀粉-裂解酶（CSE）是一种极有效的促血管生成血管扩张剂。我们最初贴上本地 CBS/H2S的产生可以填充NO在怀孕期间介导UA血管舒张的机制。的确，我们报告说，通过选择性上调EC和 SM CBS但在体内的动物（大鼠和母羊）和女性中的CSE表达不得，H2S刺激依赖于加压的UA的妊娠词典。在PE的动物模型和患有PE的女性的动物模型中，我们发现孕妇的肌层UA CBS/H2S显着下调。但是，研究在子宫血液动力学中的H2S上仍处于起步阶段。需要回答许多重要的关键问题在正常怀孕和PE中，CBS/H2S信号传导的身体和病理生理作用之前可以确定。在这个新的RO1中，我们建议测试一种增强UA EC和SM的新假设 CBS/H2S生产通过与血管相互作用来介导与妊娠相关的UA词典内皮生长因子和EC ENOS-NO和下调UA CBS/H2S信号传导有助于 PE中的血管功能障碍。我们将通过多学科翻译方法检验该假设与生化，细胞，分子，物理和药物方法以及大鼠模型中的生化，物理和药物体内，新鲜孤立的人和大鼠UA环，新型人类UA EC（HUAEC）和平滑肌细胞（HUASMC）体外模型，以及正常性与PE孕妇的肌层UAS。我们有一个杰出团队具有该领域的长期生产协作研究的记录和独特完成这个令人兴奋和重要的项目所需的工具。我们相信小说的研究概述了该RO1将提供新数据，以填补有关物理和病理生理角色的知识差距子宫血流动力学调节中的H2S和该知识将为临床提供引人注目的理由试验以探索H2S在PE高风险的女性中的治疗潜力。