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:
- 金额:$ 42.63万
- 依托单位:
- 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:
- 关键词:AnabolismAnimal ModelAnimalsArteriesBathingBiochemicalBiopsyBlood VesselsBlood flowCardiovascular systemClinical TrialsCoculture TechniquesCoupledCystathionineCysteineDataEndothelial CellsEndotheliumEnzymesEstrogensFamilyFetal Growth RetardationFetusFunctional disorderGenetic TranscriptionHumanHydrogen SulfideHypertensionImpairmentIn VitroKnowledgeLyaseMediatingMediator of activation proteinMethodsModelingMolecularMyographyMyometrialNitric OxideNutrientOrganOxidesOxygenPharmacologyPhysiologicalPlayPotassium ChannelPre-EclampsiaPregnancyPregnant WomenProductionRat-1RattusRegulationReportingResearchRoleSignal TransductionSmooth MuscleSmooth Muscle MyocytesStructureSymptomsSystemTestingTherapeuticTherapeutic InterventionUltrasonographyUp-RegulationUterusVascular DiseasesVascular Endothelial Growth Factor Receptor-1Vascular Endothelial Growth FactorsVasodilationVasodilator AgentsWomanWorkangiogenesiscohesionhemodynamicshigh riskin vitro Modelin vivoin vivo Modelinfancymultidisciplinarymyometriumnormotensivenoveloverexpressionpregnancy disorderpregnancy healthpregnantpressurepreventtooltranslational 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.
项目总结
项目成果
期刊论文数量(0)
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{{ truncateString('DONGBAO CHEN', 18)}}的其他基金
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
- 批准号:
10454412 - 财政年份:2021
- 资助金额:
$ 42.63万 - 项目类别:
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
- 批准号:
10646404 - 财政年份:2021
- 资助金额:
$ 42.63万 - 项目类别:
Caveolin-1, Caveolae and Placental Angiogenesis
Caveolin-1、Caveolae 和胎盘血管生成
- 批准号:
6821496 - 财政年份:2004
- 资助金额:
$ 42.63万 - 项目类别:
Caveolin-1, Caveolae and Placental Angiogenesis
Caveolin-1、Caveolae 和胎盘血管生成
- 批准号:
7078579 - 财政年份:2004
- 资助金额:
$ 42.63万 - 项目类别:
Caveolin-1, Caveolae and Placental Angiogenesis
Caveolin-1、Caveolae 和胎盘血管生成
- 批准号:
7240598 - 财政年份:2004
- 资助金额:
$ 42.63万 - 项目类别:
Caveolin-1, Caveolae and Placental Angiogenesis
Caveolin-1、Caveolae 和胎盘血管生成
- 批准号:
7645914 - 财政年份:2004
- 资助金额:
$ 42.63万 - 项目类别:
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