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: 10689249
• 负责人: VINICIO A DE JESUS PEREZ
• 金额: $ 70.79万
• 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/10689249
• 关键词: Affect; BMPR2 gene; Binding; Blood Vessels; Blood capillaries; CRISPR/Cas technology; CSPG4 gene; Calcium Signaling; Cardiac; Cell Communication; Cells; Chronic; Clinical; Coculture Techniques; Development; Disease; Endothelial Cells; Endothelium; Epigenetic Process; Event; Female of child bearing age; Functional disorder; Gene Expression; 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; Signaling Protein; Surface; Testing; Tissues; Transgenic Mice; Vascular remodeling; Ventricular; WNT5A gene; Work; angiogenesis; 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; pulmonary artery endothelial cell; pyrosequencing; receptor; recruit; response; right ventricular failure; right ventricular remodeling; single nucleus RNA-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）是一种以肺动脉高压升高为特征的危及生命的疾病

项目成果

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: American journal of respiratory cell and molecular biology
• 影响因子: 6.4
• 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: COMPREHENSIVE PHYSIOLOGY
• 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: American journal of respiratory and critical care medicine
• 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: Current opinion in pulmonary medicine
• 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: American journal of respiratory cell and molecular biology
• 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