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

• 批准号: 10619368
• 负责人: VINICIO A DE JESUS PEREZ
• 金额: $ 7.17万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-20 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619368
• 关键词: Affect; Blood Vessels; Cardiopulmonary; Cell Differentiation process; Cells; Cytoplasmic Tail; Disease; Endothelial Cells; Endothelium; Epigenetic Process; Female of child bearing age; Genetic Transcription; Integrins; KDR gene; Life; Ligands; Lung; Morphogenesis; Output; Pathogenesis; Pathologic; Pathway interactions; Patients; Process; Receptor Protein-Tyrosine Kinases; Recombinants; Recovery; Research Project Grants; Right Ventricular Function; Role; Signal Transduction; Supplementation; Therapeutic; Tissues; Vascular Endothelial Growth Factors; Ventricular; Work; angiogenesis; cell motility; endothelial dysfunction; improved; lung microvascular endothelial cells; lung pressure; planar cell polarity; prevent; pulmonary arterial hypertension; response; restoration; right ventricular failure

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）是一种危及生命的疾病，其特征是肺动脉高压（PAH）异常升高， 肺动脉压力和右心室（RV）衰竭。不适当的血管生成是一个关键的病理特征 PAH与内皮功能障碍和肺和RV微血管进行性丢失相关。 血管生成是新血管从现有血管产生的过程，主要由VEGF驱动 发信号。血管内皮细胞对VEGF-A的反应是分化成尖端细胞，高度运动的细胞， 发芽和伸长。我们之前的R 01建立在PMVEC形成尖端细胞的假设上， 需要VEGF和Wnt/平面细胞极性（Wnt/PCP）之间的串扰，这是一种负责 在组织形态发生过程中协调细胞运动。我们证明，Wnt/PCP激活在 PMVEC由配体Wnt 7a和ROR 2之间的相互作用驱动，ROR 2是一种酪氨酸激酶受体， 磷酸化内皮VEGFR 2胞质结构域中的残基以增加VEGF信号输出。 我们发现，与健康供者相比，VEGF-A诱导的尖端细胞形成和血管生成明显减少。 PAH患者的肺微血管内皮细胞（PMVEC）显著减少。最 重要的是，补充重组Wnt 7a或恢复PAH PMVEC中ROR 2表达 导致VEGF-A应答的恢复，这使我们得出结论，Wnt 7a/ROR 2信号传导是VEGF-A应答所必需的。 在PMVEC中适当的VEGF信号传导激活和血管生成反应。 本次更新将重点阐明调控Wnt 7a/ROR 2的转录和表观遗传机制 在健康和PAH PMVEC中的表达（目的1），ROR 2和整合素之间的相互作用是如何需要的， 建立功能性肺内皮屏障（Aim 2），以及Wnt 7a/ROR 2作为关键促血管生成因子的关键作用。 在RV适应PAH期间支持代偿性血管生成的血管生成机制（目的3）。的 这项更新中的研究将证实Wnt 7a/ROR 2信号转导作为主要调节因子的作用， 心肺血管生成，并证明恢复Wnt 7a/ROR 2的治疗潜力 信号传导，以防止PAH中的小血管损失并改善RV功能。