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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

基本信息

批准号：
10869189
负责人：
VINICIO A DE JESUS PEREZ
金额：
$ 11.62万
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：
2017-02-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10869189
关键词：
Adherens Junction Affect Animal Model Blood Vessels Blood capillaries Cardiopulmonary Cardiovascular system Cell Differentiation process Cell Extracts Cell model Cells Clinical Complex Cytoplasmic Tail DNA DNA Methylation Disease Echocardiography Endothelial Cells Endothelium Epigenetic Process Equilibrium Female of child bearing age Fluorescence Resonance Energy Transfer Focal Adhesions Genes Genetic Genetic Transcription Goals Histone Acetylation Histone Deacetylation Human Hypermethylation Hypoxia Hypoxia Inducible Factor Integrins KDR gene Knockout Mice Life Ligands Lung Measures Messenger RNA Microfluidics Modeling Molecular Morphogenesis Mus Outcome Output Pathogenesis Pathologic Pathway interactions Patients Permeability Phosphorylation Process Proteins Proteomics Pulmonary Hypertension Rattus Receptor Protein-Tyrosine Kinases Recombinants Recovery Regulation Repression Research Project Grants Right Ventricular Function Role Signal Transduction Supplementation Testing Therapeutic Tissues VEGFA gene Vascular Endothelial Growth Factors Vascular Endothelium Vascular remodeling Ventricular Work angiogenesis cell motility chromatin immunoprecipitation density endothelial dysfunction epigenetic regulation exosome improved lung microvascular endothelial cells lung pressure novel planar cell polarity prevent pulmonary arterial hypertension pulmonary artery endothelial cell pyrosequencing response restoration right ventricular failure sensor therapeutic evaluation

项目摘要

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by abnormally elevated pulmonary pressures and right ventricular (RV) failure. Inappropriate angiogenesis is a key pathological feature of PAH associated with endothelial dysfunction and progressive loss of pulmonary and RV microvessels. Angiogenesis is the process by which new vessels arise from existing vessels and is mainly driven by VEGF signaling. In response to VEGF-A, endothelial cells differentiate into tip cells, highly motile cells that direct vessel sprouting and elongation. Our previous R01 was built on the hypothesis that tip cell formation by PMVECs requires crosstalk between the VEGF and the Wnt/planar cell polarity (Wnt/PCP), a pathway responsible for coordinating cell movements during tissue morphogenesis. We demonstrated that Wnt/PCP activation in PMVECs is driven by the interaction between the ligand Wnt7a and ROR2, a tyrosine kinase receptor that phosphorylates residues in the endothelial VEGFR2 cytoplasmic domain to augment VEGF signaling output. We found that, compared to healthy donors, tip cell formation and angiogenesis in response to VEGF-A was significantly reduced in pulmonary microvascular endothelial cells (PMVEC) from PAH patients. Most importantly, supplementation with recombinant Wnt7a or restoration of ROR2 expression in PAH PMVECs results in recovery of the VEGF-A response, leading us to conclude that Wnt7a/ROR2 signaling is required for appropriate VEGF signaling activation and angiogenic response in PMVECs. This renewal will focus on elucidating the transcriptional and epigenetic mechanisms that regulate Wnt7a/ROR2 expression in healthy and PAH PMVECs (Aim 1), how interaction between ROR2 and integrins is required to establish a functional lung endothelial barrier (Aim 2), and the critical role of Wnt7a/ROR2 as a key pro- angiogenic mechanism that supports compensatory angiogenesis during RV adaptation to PAH (Aim 3). The studies in this renewal will confirm the role of Wnt7a/ROR2 signaling as a master regulator of cardiopulmonary angiogenesis and demonstrate the therapeutic potential of restoring Wnt7a/ROR2 signaling to prevent small vessel loss and improve RV function in PAH.

肺动脉高压（PAH）是一种以异常增高为特征的危及生命的疾病