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：
10522873
负责人：
VINICIO A DE JESUS PEREZ
金额：
$ 73.28万
依托单位：
STANFORD UNIVERSITY
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：
https://reporter.nih.gov/project-details/10522873
关键词：
Affect BMPR2 gene Binding Blood Vessels Blood capillaries CRISPR/Cas technology CSPG4 gene Calcium Signaling Cardiac Cell Communication Cell Nucleus Cells Chronic Clinical Development Disease Endothelial Cells Endothelium Epigenetic Process Event Female of child bearing age Functional disorder Gene Expression Genes Genetic Transcription Goals Histone Deacetylation Hyperplasia Hypoxia Knockout Mice Life Ligands Lung Methylation Morphogenesis Mus Natural regeneration Pathogenesis Pathology Pathway interactions Patient-Focused Outcomes Patients Pattern Pericytes Physiological Play Production Pulmonary Circulation Pulmonary Hypertension Rattus Recovery Repression Research Project Grants Role Severities Signal Pathway Signal Transduction Small Nuclear RNA Surface Testing Tissues Transgenic Mice Vascular remodeling Ventricular WNT5A gene Work angiogenesis base chromatin immunoprecipitation density endothelial dysfunction epigenetic regulation exosome genomic locus improved insight lung microvascular endothelial cells lung pressure novel therapeutics overexpression planar cell polarity prevent pulmonary arterial hypertension pyrosequencing receptor recruit response right ventricular failure right ventricular remodeling transcriptome 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压力和右心衰竭。 PAH 病理学的一个标志是进行性损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，它们相互作用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。我们的研究表明，无法建立适当的内皮-周细胞（EC-PC）相互作用与 PAH 中肺小血管损失和血管生成不足，使我们推测，针对协调 EC-PC 相互作用的机制可能为 PAH 开辟新的治疗机会。我们有证明功能失调的 Wnt/平面细胞极性 (PCP) 信号传导导致 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 Wnt5a 通过周细胞中 ROR2 依赖性 Wnt/PCP 激活来招募肺周细胞。相比健康供体中，Wnt5a 产生和 ROR2 依赖性 Wnt/PCP 激活均显着减少分别为 PAH PMVEC 和周细胞。我们还发现小鼠内皮特异性 Wnt5a 缺失与失代偿性 RV 衰竭相关，其特征是 EC-PC 相互作用中断和 RV 减少毛细血管密度。根据我们的发现，我们假设 Wnt/PCP 信号传导的丧失会导致肺损伤 PAH 中的 RV 血管功能障碍是通过破坏 EC-PC 相互作用的建立来实现的血管生成。在本次更新中，我们计划：（目标 1）阐明造成不当行为的机制 PAH PMVEC 表达 Wnt5a，（目标 2）阐明 ROR2 功能失调的机制 PAH 周细胞中的活性，以及（目标 3）证明 Wnt5a/ROR2 信号在 RV 重塑中发挥关键作用和血管生成对 PAH 的反应。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，以促进再生失去的血管，防止病情进展并改善患者的临床结果毁灭性的疾病。