Activation of the Wnt/planar cell polarity pathway is required for pericyte recruitment during pulmonary angiogenesis.
Activation of the Wnt/planar cell polarity pathway is required for pericyte recruitment during pulmonary angiogenesis.
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DOI：
10.1016/j.ajpath.2014.09.013
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发表时间：
2015
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影响因子：
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通讯作者：
K. Yuan;M. Orcholski;Cristina Panaroni;Eric M. Shuffle;N. Huang;Xinguo Jiang;W. Tian;Eszter K Vladar;Lingli Wang;M. Nicolls;Joy Y Wu;V. A. de Jesus Perez
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文献类型：
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作者：
K. Yuan;M. Orcholski;Cristina Panaroni;Eric M. Shuffle;N. Huang;Xinguo Jiang;W. Tian;Eszter K Vladar;Lingli Wang;M. Nicolls;Joy Y Wu;V. A. de Jesus Perez
周细胞是血管周围的细胞，定位于毛细血管，促进血管成熟，它们的缺失会导致血管损失。内皮-周细胞相互作用受损是否导致肺动脉高压（PAH）患者小血管损失尚不清楚。使用3g5特异性，免疫球蛋白g包被磁珠，我们从健康受试者和PAH患者的肺中分离周细胞，然后进行谱系验证。植入健康肺微血管内皮细胞的PAH周细胞不能与内皮管结合，导致血管网络比健康周细胞更小。在通过活体成像和伤口愈合研究证实了内皮细胞的异常极化后，我们筛选了PAH周细胞中Wnt/平面细胞极性（PCP）通路的异常，该通路已被证明可以调节肺血管中的细胞运动和极性。PAH周细胞卷曲7 （Fzd7）和cdc42的表达减少，这两个基因对Wnt/PCP激活至关重要。在健康体外周细胞素和小鼠血管生成模型中同时敲低Fzd7和cdc42，肺微血管内皮细胞的运动性和极化降低，而在PAH周细胞中恢复这两个基因，内皮-周细胞的关联得到改善，血管网络更大。这些研究表明，在肺血管生成过程中，周细胞的运动和极性受Wnt/PCP激活的调节，这可以有针对性地预防PAH中的血管损失。
Pericytes are perivascular cells localized to capillaries that promote vessel maturation, and their absence can contribute to vessel loss. Whether impaired endothelial–pericyte interaction contributes to small vessel loss in pulmonary arterial hypertension (PAH) is unclear. Using 3G5-specific, immunoglobulin G–coated magnetic beads, we isolated pericytes from the lungs of healthy subjects and PAH patients, followed by lineage validation. PAH pericytes seeded with healthy pulmonary microvascular endothelial cells failed to associate with endothelial tubes, resulting in smaller vascular networks compared to those with healthy pericytes. After the demonstration of abnormal polarization toward endothelium via live-imaging and wound-healing studies, we screened PAH pericytes for abnormalities in the Wnt/planar cell polarity (PCP) pathway, which has been shown to regulate cell motility and polarity in the pulmonary vasculature. PAH pericytes had reduced expression of frizzled 7 (Fzd7) andcdc42, genes crucial for Wnt/PCP activation. With simultaneous knockdown of Fzd7 and cdc42 in healthy pericytesin vitroand in a murine model of angiogenesis, motility and polarization toward pulmonary microvascular endothelial cells were reduced, whereas with restoration of both genes in PAH pericytes, endothelial–pericyte association was improved, with larger vascular networks. These studies suggest that the motility and polarity of pericytes during pulmonary angiogenesis are regulated by Wnt/PCP activation, which can be targeted to prevent vessel loss in PAH.