Endothelial-pericyte interactions in the pathogenesis of pulmonary arterial hypertension
肺动脉高压发病机制中的内皮-周细胞相互作用
基本信息
- 批准号:10689249
- 负责人:
- 金额:$ 70.79万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-12-07 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AffectBMPR2 geneBindingBlood VesselsBlood capillariesCRISPR/Cas technologyCSPG4 geneCalcium SignalingCardiacCell CommunicationCellsChronicClinicalCoculture TechniquesDevelopmentDiseaseEndothelial CellsEndotheliumEpigenetic ProcessEventFemale of child bearing ageFunctional disorderGene ExpressionGenetic TranscriptionGoalsHistone DeacetylationHyperplasiaHypoxiaKnockout MiceLifeLigandsLungMethylationMorphogenesisMusNatural regenerationPathogenesisPathologyPathway interactionsPatient-Focused OutcomesPatientsPatternPericytesPhysiologicalPlayProductionPulmonary CirculationPulmonary HypertensionRattusRecoveryRepressionResearch Project GrantsRoleSeveritiesSignal PathwaySignal TransductionSignaling ProteinSurfaceTestingTissuesTransgenic MiceVascular remodelingVentricularWNT5A geneWorkangiogenesischromatin immunoprecipitationdensityendothelial dysfunctionepigenetic regulationexosomegenomic locusimprovedinsightlung microvascular endothelial cellslung pressurenovel therapeuticsoverexpressionplanar cell polaritypreventpulmonary arterial hypertensionpulmonary artery endothelial cellpyrosequencingreceptorrecruitresponseright ventricular failureright ventricular remodelingsingle nucleus RNA-sequencing
项目摘要
Pulmonary arterial hypertension (PAH) is a life-threatening disorder characterized by elevated pulmonary
pressures and right heart failure. A hallmark of PAH pathology is progressive loss and inappropriate regeneration
of pulmonary and right ventricular (RV) microvessels. Pericytes are highly specialized mural cells that interact
with endothelial cells to provide structural support and facilitate vessel maturation during angiogenesis. Our
studies show that inability to establish proper endothelial-pericyte (EC-PC) interactions is associated with
pulmonary small vessel loss and insufficient angiogenesis in PAH, leading us to speculate that targeting the
mechanisms that orchestrate EC-PC interactions could open new therapeutic opportunities for PAH. We have
demonstrated that dysfunctional Wnt/planar cell polarity (PCP) signaling contributes to small vessel loss in PAH
by disrupting lung EC-PC interactions. We found that pulmonary microvascular endothelial cells (PMVECs)
release Wnt5a to recruit lung pericytes via ROR2-dependent Wnt/PCP activation in pericytes. Compared to
healthy donors, both Wnt5a production and ROR2-dependent Wnt/PCP activation are significantly reduced in
PAH PMVECs and pericytes, respectively. We also found that endothelial-specific Wnt5a deletion in mice was
associated with decompensated RV failure characterized by disrupted EC-PC interactions and reduced RV
capillary density. Based on our findings, we hypothesize that loss of Wnt/PCP signaling contributes to lung
and RV vessel dysfunction in PAH by disrupting the establishment of EC-PC interactions and
angiogenesis. In this renewal, we plan to: (Aim 1) Elucidate the mechanisms responsible for inappropriate
Wnt5a expression by PAH PMVECs, (Aim 2) Elucidate the mechanisms responsible for dysfunctional ROR2
activity in PAH pericytes, and (Aim 3) Demonstrate that Wnt5a/ROR2 signaling plays a key role in RV remodeling
and angiogenesis in response to PAH. Understanding how Wnt/PCP orchestrates endothelial-pericyte
interactions will provide insight into the PAH pathogenesis and open new therapeutic opportunities to promote
regeneration of lost vessels, prevent progression and improve clinical outcomes for patients afflicted with this
devastating disease.
肺动脉高压(PAH)是一种危及生命的疾病,其特征是肺动脉高压(PAH)升高,
血压和右心衰竭PAH病理学的标志是进行性丢失和不适当的再生
肺和右心室(RV)微血管。周细胞是高度特化的壁细胞,
与内皮细胞一起提供结构支持并促进血管生成过程中的血管成熟。我们
研究表明,不能建立适当的内皮-周细胞(EC-PC)相互作用与
肺小血管损失和血管生成不足,使我们推测,针对肺动脉高压,
协调EC-PC相互作用的机制可能为PAH开辟新的治疗机会。我们有
表明功能失调的Wnt/平面细胞极性(PCP)信号通路有助于PAH中的小血管损失
通过破坏肺EC-PC相互作用。我们发现肺微血管内皮细胞(PMVEC)
释放Wnt 5a以通过周细胞中的ROR 2依赖性Wnt/PCP活化来募集肺周细胞。相比
在健康供体中,Wnt 5a的产生和ROR 2依赖的Wnt/PCP活化均显著降低,
PAH PMVEC和周细胞。我们还发现,小鼠内皮特异性Wnt 5a缺失,
与以EC-PC相互作用中断和RV降低为特征的失代偿性RV衰竭相关
毛细管密度基于我们的研究结果,我们假设Wnt/PCP信号转导的缺失有助于肺
通过破坏EC-PC相互作用的建立,
血管生成在这次更新中,我们计划:(目标1)阐明负责不适当的机制
PAH PMVEC的Wnt 5a表达,(目的2)阐明ROR 2功能障碍的机制
目的3:证实Wnt 5a/ROR 2信号通路在RV重塑中起关键作用
和血管生成。了解Wnt/PCP如何协调内皮-周细胞
相互作用将提供对PAH发病机制的深入了解,并开辟新的治疗机会,
再生失去的血管,防止进展和改善患有这种疾病的患者的临床结果。
毁灭性的疾病
项目成果
期刊论文数量(31)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Long-Term Right Ventricular Adaptation to Postnatal Hyperoxia: Too Much of a Good Thing?
右心室对产后高氧的长期适应:好事太多了?
- DOI:10.1165/rcmb.2016-0429ed
- 发表时间:2017
- 期刊:
- 影响因子:6.4
- 作者:Perez,VinicioAdeJesus
- 通讯作者:Perez,VinicioAdeJesus
Lung Pericytes in Pulmonary Vascular Physiology and Pathophysiology.
- DOI:10.1002/cphy.c200027
- 发表时间:2021-06-30
- 期刊:
- 影响因子:5.8
- 作者:Yuan, Ke;Agarwal, Stuti;Chakraborty, Ananya;Condon, David F.;Patel, Hiral;Zhang, Serena;Huang, Flora;Mello, Salvador A.;Kirk, Obadiah I.;Vasquez, Rocio;Perez, Vinicio A. de Jesus
- 通讯作者:Perez, Vinicio A. de Jesus
Use of Wearables and Implantable Devices to Monitor Pulmonary Health in the Outpatient Setting.
使用可穿戴设备和植入设备在门诊环境中监测肺部健康状况。
- DOI:10.1164/rccm.202102-0462rr
- 发表时间:2022
- 期刊:
- 影响因子:24.7
- 作者:Glinskii,Vladimir;Lyn,Raquel;Thomas,Christopher;deJesusPerez,VinicioA
- 通讯作者:deJesusPerez,VinicioA
Methamphetamine and the risk of pulmonary arterial hypertension.
- DOI:10.1097/mcp.0000000000000513
- 发表时间:2018-09
- 期刊:
- 影响因子:3.3
- 作者:Ramirez RL 3rd;Perez VJ;Zamanian RT
- 通讯作者:Zamanian RT
Mural Cell SDF1 Signaling Is Associated with the Pathogenesis of Pulmonary Arterial Hypertension.
壁细胞 SDF1 信号转导与肺动脉高压的发病机制相关。
- DOI:10.1165/rcmb.2019-0401oc
- 发表时间:2020
- 期刊:
- 影响因子:6.4
- 作者:Yuan,Ke;Liu,Yu;Zhang,Yue;Nathan,Abinaya;Tian,Wen;Yu,Joyce;Sweatt,AndrewJ;Shamshou,ElyaA;Condon,David;Chakraborty,Ananya;Agarwal,Stuti;Auer,Natasha;Zhang,Serena;Wu,JosephC;Zamanian,RohamT;Nicolls,MarkR;deJesusPerez,V
- 通讯作者:deJesusPerez,V
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VINICIO A DE JESUS PEREZ其他文献
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{{ truncateString('VINICIO A DE JESUS PEREZ', 18)}}的其他基金
The Wnt7a/ROR2 axis in the pathogenesis of pulmonary arterial hypertension
Wnt7a/ROR2轴在肺动脉高压发病机制中的作用
- 批准号:
10619368 - 财政年份:2022
- 资助金额:
$ 70.79万 - 项目类别:
A novel microfluidic platform to study exosome biology in PAH.
一种用于研究多环芳烃外泌体生物学的新型微流体平台。
- 批准号:
10158068 - 财政年份:2021
- 资助金额:
$ 70.79万 - 项目类别:
A novel microfluidic platform to study exosome biology in PAH.
一种用于研究多环芳烃外泌体生物学的新型微流体平台。
- 批准号:
10378161 - 财政年份:2021
- 资助金额:
$ 70.79万 - 项目类别:
Stanford Undergraduate URM Summer Cardiovascular Research Program
斯坦福大学本科生夏季心血管研究项目
- 批准号:
10246191 - 财政年份:2019
- 资助金额:
$ 70.79万 - 项目类别:
Stanford Undergraduate URM Summer Cardiovascular Research Program
斯坦福大学本科生夏季心血管研究项目
- 批准号:
10021034 - 财政年份:2019
- 资助金额:
$ 70.79万 - 项目类别:
Stanford Undergraduate URM Summer Cardiovascular Research Program
斯坦福大学本科生夏季心血管研究项目
- 批准号:
10471319 - 财政年份:2019
- 资助金额:
$ 70.79万 - 项目类别:
Stanford Undergraduate URM Summer Cardiovascular Research Program
斯坦福大学本科生夏季心血管研究项目
- 批准号:
10686866 - 财政年份:2019
- 资助金额:
$ 70.79万 - 项目类别:
Endothelial-pericyte interactions in the pathogenesis of pulmonary arterial hypertension
肺动脉高压发病机制中的内皮-周细胞相互作用
- 批准号:
10522873 - 财政年份:2017
- 资助金额:
$ 70.79万 - 项目类别:
The Wnt7a/ROR2 axis in the pathogenesis of pulmonary arterial hypertension
Wnt7a/ROR2轴在肺动脉高压发病机制中的作用
- 批准号:
10869189 - 财政年份:2017
- 资助金额:
$ 70.79万 - 项目类别:
The Wnt7a/ROR2 axis in the pathogenesis of pulmonary arterial hypertension
Wnt7a/ROR2轴在肺动脉高压发病机制中的作用
- 批准号:
10609932 - 财政年份:2017
- 资助金额:
$ 70.79万 - 项目类别:
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