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，其特征是异常升高 肺压力和右室(RV)衰竭不适当的血管生成是一个重要的病理特征。 PAH与内皮功能障碍和进行性肺和右室微血管丢失有关。 血管生成是由现有血管生成新血管的过程，主要由血管内皮生长因子驱动 发信号。作为对血管内皮生长因子-A的响应，内皮细胞分化为TIP细胞，即指导血管的高度运动性细胞 发芽和伸长。我们之前的R01建立在假设PMVECs形成TIP细胞的基础上 需要在血管内皮生长因子和Wnt/平面细胞极性(Wnt/PCP)之间的串扰，这是负责 在组织形态发生过程中协调细胞运动。我们证明了Wnt/PCP在 PMVECs是由配体Wnt7a和ROR2之间的相互作用驱动的，ROR2是一种酪氨酸激酶受体， 磷酸化内皮细胞VEGFR2胞浆结构域中的残基，以增加VEGF信号输出。 我们发现，与健康供者相比，TIP细胞的形成和血管生成对血管内皮生长因子-A的反应 PAH患者肺微血管内皮细胞(PMVEC)明显减少。多数 重要的是，在PAH PMVEC中补充重组WNT7a或恢复ROR2的表达 导致血管内皮生长因子-A反应的恢复，使我们得出结论，Wnt7a/ROR2信号转导是 PMVECs中适当的血管内皮生长因子信号激活和血管生成反应。 这一更新将集中于阐明调控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和整合素之间的相互作用如何才能 建立功能性肺内皮屏障(Aim 2)，以及Wnt7a/ROR2作为关键促进因子的关键作用。 在RV适应PAH期间支持代偿性血管生成的血管生成机制(目标3)。这个 这次更新的研究将证实Wnt7a/ROR2信号作为一种主要调节因子的作用。 心肺血管生成及修复Wnt7a/ROR2的治疗潜力 在PAH中防止小血管丢失和改善RV功能的信号转导。