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，其特征是血压异常升高 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 与内皮功能障碍以及肺和右心室微血管进行性丧失相关。 血管生成是从现有血管产生新血管的过程，主要由 VEGF 驱动 发信号。响应 VEGF-A，内皮细胞分化为尖端细胞，即引导血管的高度运动细胞 发芽和伸长。我们之前的 R01 是建立在 PMVEC 形成尖端细胞的假设之上的 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。我们证明了 Wnt/PCP 激活 PMVEC 由配体 Wnt7a 和 ROR2 之间的相互作用驱动，ROR2 是一种酪氨酸激酶受体， 磷酸化内皮 VEGFR2 胞质结构域中的残基以增强 VEGF 信号输出。 我们发现，与健康供体相比，对 VEGF-A 的反应是尖端细胞形成和血管生成 PAH 患者的肺微血管内皮细胞 (PMVEC) 显着减少。最多 重要的是，补充重组 Wnt7a 或恢复 PAH PMVEC 中的 ROR2 表达 导致 VEGF-A 反应恢复，使我们得出结论，Wnt7a/ROR2 信号传导是 PMVEC 中适当的 VEGF 信号激活和血管生成反应。 此次更新将重点阐明调节 Wnt7a/ROR2 的转录和表观遗传机制 在健康和 PAH PMVEC 中的表达（目标 1），ROR2 和整合素之间如何相互作用 建立功能性肺内皮屏障（目标 2），以及 Wnt7a/ROR2 作为关键亲的关键作用 血管生成机制支持 RV 适应 PAH 期间的代偿性血管生成（目标 3）。这 此次更新的研究将证实 Wnt7a/ROR2 信号作为主调节因子的作用 心肺血管生成并证明恢复 Wnt7a/ROR2 的治疗潜力 信号传导可防止 PAH 患者小血管丢失并改善 RV 功能。