Endothelial cell polarity and extracellular matrix composition require functional ATP6AP2 during developmental and pathological angiogenesis.
Endothelial cell polarity and extracellular matrix composition require functional ATP6AP2 during developmental and pathological angiogenesis.
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DOI：
10.1172/jci.insight.154379
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发表时间：
2022-10-10
期刊：
影响因子：
8
通讯作者：
Meadows, Stryder M.
中科院分区：
文献类型：
--
作者：
Patel, Nehal R.;Rajan, K. C.;Blanks, Avery;Li, Yisu;Prieto, Minolfa C.;Meadows, Stryder M.
（Pro）肾素受体（[P]RR），也称为ATP 6AP 2，是一种单跨膜蛋白，涉及许多生物过程。然而，ATP 6AP 2在血管发育过程中的确切作用在很大程度上仍然不确定。在这里，我们使用诱导内皮细胞特异性（EC-特异性）Atp 6ap 2-KO小鼠模型，以调查在生理和病理血管生成过程中的作用，ATP 6AP 2在体内。我们观察到出生后内皮细胞中Atp 6ap 2的缺失导致细胞迁移缺陷，尖端细胞极性丧失，以及随后的视网膜血管生成障碍。在体外，Atp 6ap 2缺陷的EC同样显示细胞迁移减少，发芽受损，和有缺陷的细胞极性。从Atp 6ap 2突变小鼠分离的EC的转录谱进一步表明在血管生成、细胞迁移和细胞外基质组成中的调节作用。机制上，我们提供的证据表明，各种细胞外基质成分的表达是由ATP 6AP 2通过ERK途径控制。此外，Atp 6ap 2缺陷型视网膜在氧诱导的视网膜病变模型中表现出减少的血管重建。总的来说，我们的研究结果证明了ATP 6AP 2作为发育和病理性血管生成的调节剂的关键作用。
The (Pro)renin receptor ([P]RR), also known as ATP6AP2, is a single-transmembrane protein that is implicated in a multitude of biological processes. However, the exact role of ATP6AP2 during blood vessel development remains largely undefined. Here, we use an inducible endothelial cell–specific (EC-specific) Atp6ap2-KO mouse model to investigate the role of ATP6AP2 during both physiological and pathological angiogenesis in vivo. We observed that postnatal deletion of Atp6ap2 in ECs results in cell migration defects, loss of tip cell polarity, and subsequent impairment of retinal angiogenesis. In vitro, Atp6ap2-deficient ECs similarly displayed reduced cell migration, impaired sprouting, and defective cell polarity. Transcriptional profiling of ECs isolated from Atp6ap2 mutant mice further indicated regulatory roles in angiogenesis, cell migration, and extracellular matrix composition. Mechanistically, we provided evidence that expression of various extracellular matrix components is controlled by ATP6AP2 via the ERK pathway. Furthermore, Atp6ap2-deficient retinas exhibited reduced revascularization in an oxygen-induced retinopathy model. Collectively, our results demonstrate a critical role of ATP6AP2 as a regulator of developmental and pathological angiogenesis.
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