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
• 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
• 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

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)是一种以肺高压为特征的危及生命的疾病。 血压和右心衰竭。PAH病理的一个特点是进行性丢失和不适当的再生 肺和右室(RV)微血管。周细胞是高度特化的壁细胞，它们相互作用 血管内皮细胞在血管生成过程中提供结构支持和促进血管成熟。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中肺小血管丢失和血管生成不足，使我们推测靶向 协调EC-PC相互作用的机制可能为PAH打开新的治疗机会。我们有 证实Wnt/平面细胞极性(PCP)信号转导功能障碍与PAH小血管丢失有关 通过破坏肺内EC-PC之间的相互作用。我们发现肺微血管内皮细胞(PMVECs) 释放Wnt5a，通过在周细胞中激活依赖于ROR2的Wnt/PCP来招募肺周细胞。与.相比 健康供者，Wnt5a的产生和依赖ROR2的Wnt/PCP的激活在 PAH分别为PMVECs和周细胞。我们还发现，在小鼠中，内皮特异性Wnt5a缺失是 与失代偿性RV故障相关，特征为EC-PC交互中断和RV减少 毛细血管密度。根据我们的发现，我们假设Wnt/PCP信号的丢失对肺有贡献 通过扰乱EC-PC相互作用和RV血管功能障碍 血管生成。在这次更新中，我们计划：(目标1)阐明造成不当行为的机制 PAH PMVECs Wnt5A的表达(目的2)阐明ROR2功能障碍的机制 在PAH周细胞中的活性，以及(Aim 3)表明Wnt5a/ROR2信号在RV重塑中起关键作用 和血管生成对PAH的反应。了解Wnt/PCP如何协调内皮细胞-周细胞 互动将提供对PAH发病机制的洞察，并打开新的治疗机会，以促进 再生丢失的血管，防止病情进展，改善患者的临床预后 毁灭性的疾病。