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

肺动脉高压（PAH）是一种与异常增高相关的危及生命的疾病

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.