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）是一种威胁生命的疾病，其特征是肺部升高 压力和右心衰竭。 PAH病理学的标志是进步损失和不适当的再生 肺部和右心（RV）微血管。周细胞是高度专业的壁细胞，相互作用 用内皮细胞提供结构支撑并促进血管生成期间血管成熟。我们的 研究表明，无法建立适当的内皮周期（EC-PC）相互作用与 PAH中的肺小血管损失和血管生成不足，导致我们推测针对的是 协调EC-PC相互作用的机制可以为PAH打开新的治疗机会。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通过周细胞中的ROR2依赖性WNT/PCP激活募集肺周周。相比 健康的供体，Wnt5a的产生和依赖ROR2的Wnt/PCP激活都大大降低 PAH PMVEC和周细胞。我们还发现，小鼠内皮特异性的Wnt5a缺失是 与代表EC-PC相互作用中断和RV减少的代表性的RV失败相关 毛细管密度。根据我们的发现，我们假设Wnt/PCP信号的丧失有助于肺 通过破坏EC-PC相互作用的建立和 血管生成。在此续约中，我们计划：（目标1）阐明负责不适当的机制 pah pmvecs的Wnt5a表达，（AIM 2）阐明了负责ROR2功能失调的机制 PAH周细胞的活性，（AIM 3）证明Wnt5a/ROR2信号在RV重塑中起关键作用 以及对PAH的血管生成。了解WNT/PCP如何编排内皮 - 周期性 互动将为PAH发病机理和开放新的治疗机会提供洞察力以促进 损失血管的再生，防止进展并改善患有这种困扰的患者的临床结果 毁灭性疾病。