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：
10274204
负责人：
DONGBAO CHEN
金额：
$ 42.63万
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/10274204
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 Structure Symptoms System Testing Therapeutic Therapeutic Intervention Ultrasonography 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

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.

项目概要一旦受孕，女性的心血管系统就会发生巨大的结构和功能变化，适应快速生长的胎儿日益增长的需求，导致子宫动脉深度扩张例如，子宫血流量（UBF）的急剧增加是妊娠健康的限制因素。因为怀孕期间 UBF 上升不足会导致宫内生长受限，自 1900 年代以来，先兆子痫 (PE) 的特点是全身内皮损伤和血管功能障碍。大量研究表明，局部内皮一氧化氮（NO）介导的血管舒张是主要的作用。然而，局部 NO 产生的阻断只能部分抑制基线。妊娠相关的 UBF 升高，表明其他介质也参与其中。硫化物（H2S），主要由L-半胱氨酸通过两种关键酶合成：胱硫醚-合酶（CBS）和胱硫醚-裂解酶（CSE）是一种极其有效的促血管生成血管扩张剂，我们最初将其定位于局部。 CBS/H2S 的产生可以填补 NO 背后的机制，从而介导怀孕期间 UA 血管舒张。我们报道妊娠通过选择性上调 EC 和 UA 显着增强 UA H2S 生物合成 SM CBS 在动物（大鼠和母羊）和女性体内表达，但不表达 CSE，并且 H2S 会刺激在 PE 动物模型和患有 PE 的女性中，我们发现妊娠依赖性 UA 离体扩张。然而，研究发现妊娠增强的子宫肌层UA CBS/H2S 显着下调。关于 H2S 子宫血流动力学的研究仍处于起步阶段，许多重要的关键问题需要得到解答；在正常妊娠和 PE 中 CBS/H2S 信号传导的生理和病理生理作用之前在这个新的 RO1 中，我们建议测试一个增强 UA EC 和 SM 的新假设。 CBS/H2S 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 以及下调的 UA CBS/H2S 信号传导有助于我们将通过多学科转化方法来检验这一假设。采用生化、细胞、分子、生理和药理学方法与大鼠模型相结合体内、新鲜分离的人和大鼠 UA 环、离体、新型人 UA EC (hUAEC) 和平滑肌细胞 (hUASMC) 体外模型，以及血压正常孕妇与 PE 孕妇的子宫肌层 UA。优秀的团队，在该领域拥有长期富有成效的合作研究记录，并且具有独特的我们相信完成这个令人兴奋且重要的项目所需的工具。该 RO1 将提供新数据，以填补关于生理和病理生理作用的知识空白 H2S 在子宫血流动力学调节中的作用，这一知识将为临床提供令人信服的理论依据探索 H2S 对 PE 高危女性的治疗潜力的试验。