The role of the Wnt5a/ROR2 in the pathogenesis of pulmonary arterial hypertension.

肺动脉高压(PAH)是一种与异常升高相关的危及生命的疾病。 肺微血管进行性丧失和再生受损所致的肺压力。 在形成功能性血管网络中的一个关键事件是用周细胞包裹血管管，高度 专门的壁细胞，直接与内皮细胞相互作用，为新生的 形成了血管。许多研究试图阐明小血管丢失背后的机制 以肺微血管内皮细胞(PMVECs)在PAH中的作用为中心，但对 Date已经探索了周细胞在疾病中的作用。使用一种基于磁珠的新方法 我们发现，直接从人肺中分离周细胞，与从健康人肺中分离的周细胞相比 个体，PAH周细胞在血管网络中无法迁移并与健康的PMVECs结合 队形。周细胞向血管募集的机制与激活 Wnt/平面细胞极性(PCP)，一种参与组织中细胞运动和排列的途径 队形。我们的初步研究表明PMVECs和周细胞是伴生的。 Wnt5a和ROR2在共培养中的上调认为这种Wnt/PCP配体-受体对是 肺血管生成过程中内皮细胞-周细胞相互作用的建立。我们建议(1) Wnt/PCP活化是PMVECs和周细胞组织成功能性肺组织所必需的 微血管和(2)降低Wnt/PCP活性的突变损害了术后肺血管的再生 受伤。我们将使用一种新的内皮特异性Wnt5a基因敲除的小鼠模型和基于细胞的 血管生成检测和基因编辑技术研究Wnt5a和ROR2在血管生成中的作用 正常肺血管生成过程中内皮细胞-周细胞相互作用的建立 这两个基因的失调第一次可以降低PAH周细胞建立 适当的内皮-周细胞相互作用。我们的最终目标是扩大对生物的认识 参与肺血管生成的反应，并有助于目前开发新治疗方法的努力 旨在防止和/或扭转PAH中小血管损失的战略。

Pulmonary arterial hypertension (PAH) is a life-threatening disorder that is associated with abnormal increase in pulmonary pressures resulting from progressive loss and impaired regeneration of pulmonary microvessels. A key event in the formation of functional vascular networks is coating of vascular tubes with pericytes, highly specialized mural cells that directly interact with endothelial cells to provide support and protection to newly formed blood vessels. Many studies have attempted to elucidate the mechanisms behind the small vessel loss in PAH by centering on the role of the pulmonary microvascular endothelial cells (PMVECs) but few studies to date have explored the contribution of pericytes to the disease. Using a novel magnetic bead-based method to isolate pericytes directly from human lungs we have found that, compared to pericytes isolated from healthy individuals, PAH pericytes fail to migrate and associate with healthy PMVECs during vascular network formation. The mechanism involved in the recruitment of pericytes to blood vessels is related to activation of the Wnt/Planar cell polarity (PCP), a pathway involved in orchestrating cell motility and alignment during tissue formation. Our preliminary studies have shown that PMVECs and pericytes demonstrate concomitant upregulation of Wnt5a and ROR2 in co-culture arguing that this Wnt/PCP ligand-receptor pair is necessary for establishment of endothelial-pericyte interactions during pulmonary angiogenesis. We propose that (1) activation of Wnt/PCP is necessary for PMVECs and pericytes to organize into functional pulmonary microvessels and (2) that mutations that reduce Wnt/PCP activity impair pulmonary vascular regeneration after injury. We will use a novel mouse model of endothelial-specific Wnt5a knockout together with cell-based angiogenesis assays and gene editing techniques to study the involvement of Wnt5a and ROR2 in the establishment of endothelial-pericyte interaction during normal pulmonary angiogenesis and demonstrate for the first time that dysregulation of these two genes can reduce the capacity of PAH pericytes to establish proper endothelial-pericyte interactions. Our ultimate goal is to expand the knowledge of the biological responses involved in pulmonary angiogenesis and contribute to current efforts to develop new treatment strategies aimed at preventing and/or reversing small vessel loss in PAH.