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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：
10646404
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/10646404
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 Methods Modeling Molecular Myography Myometrial Nitric Oxide Nutrient Organ Oxides Oxygen Physiological Play Potassium Channel Pre-Eclampsia Pregnancy Pregnant Women Production Productivity 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 hemodynamics high risk in vitro Model in vivo in vivo Model infancy multidisciplinary myometrium normotensive novel overexpression pharmacologic 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.

项目总结一旦怀孕，女性的心血管系统就会经历戏剧性的结构和功能变化适应快速生长的胎儿日益增长的需求，导致子宫动脉严重扩张以子宫血流量(UBF)显著增加为例。UBF是影响妊娠健康的一个限速因素因为妊娠期UBF升高不足会导致胎儿宫内发育受限子痫前期(PE)以全身性内皮损伤和血管功能障碍为特征。从1900年的S开始，大量研究表明，局部血管内皮细胞一氧化氮(NO)介导的血管扩张是主要的 UBF上升的控制机制。然而，阻断局部NO的产生只能部分抑制基线妊娠相关UBF升高，提示有其他调节因子(S)参与。内源氢气硫化物(H_2S)，主要由L-半胱氨酸通过两个关键酶合成：胱硫醚-合成酶(Cbs)和胱硫醚裂解酶(Cystathionine-lyase，CSE)是一种非常有效的血管生成前体扩张剂。我们最初认为当地的 CBS/H_2S的产生可以填补NO在孕期介导UA血管扩张的机制。的确，我们报道，怀孕通过选择性地上调EC和UA-H_2S的合成，显著增加UA-H_2S的生物合成 SM CBS但不表达CSE在动物(大鼠和绵羊)和妇女体内以及H_2S刺激体外加压UA的妊娠依赖性扩张。在PE的动物模型和患有PE的女性中，我们研究发现，妊娠增强的子宫肌层UA、CBS/H_2S的表达显著下调。然而，研究表明，关于硫化氢在子宫血流动力学中的研究仍处于初级阶段；许多重要的关键问题需要回答在CBS/H2S信号在正常妊娠和PE中的生理和病理生理学作用之前要下定决心。在这个新的RO1中，我们建议检验一个新的假设，即增强的UA、EC和SM CBS/H_2S的产生通过与血管相互作用介导妊娠相关的UA扩张内皮生长因子和EC eNOS-NO及下调的UA CBS/H_2S信号转导途径 PE中的血管功能障碍。我们将通过多学科的翻译方法来检验这一假设用生化、细胞、分子、生理和药理学方法结合大鼠模型活体、新鲜分离的人和大鼠体外UA环、新型人UA EC(HUAEC)和平滑肌细胞 (HUASMC)体外模型，以及正常血压与PE孕妇的子宫肌层UAS。我们有一个优秀的团队，在该领域拥有长期富有成效的合作研究记录，并具有独特的完成这一令人兴奋和重要的项目所需的工具。我们认为，该RO1将提供新的数据，以填补有关生理和病理生理学作用的知识空白硫化氢在子宫血流动力学调节中的作用，这一认识将为临床提供令人信服的理论基础探讨硫化氢对PE高危女性的治疗潜力。