Axl Is Essential for in-vitro Angiogenesis Induced by Vitreous From Patients With Proliferative Diabetic Retinopathy.
Axl Is Essential for in-vitro Angiogenesis Induced by Vitreous From Patients With Proliferative Diabetic Retinopathy.
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Axl 对于增殖性糖尿病视网膜病变患者玻璃体诱导的体外血管生成至关重要
DOI：
10.3389/fmed.2021.787150
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发表时间：
2021
影响因子：
3.9
通讯作者：
Lei H
中科院分区：
文献类型：
--
作者：
Wu W;Xu H;Meng Z;Zhu J;Xiong S;Xia X;Lei H
增殖性糖尿病视网膜病变（PDR）主要表现为异常视网膜前血管生成形成纤维血管膜（FVM），威胁糖尿病患者的视力； FVM 由细胞外基质和包括血管内皮细胞在内的多种细胞类型组成。 Axl 是受体酪氨酸激酶之一，可以通过细胞内途径被血管内皮生长因子-A (VEGF-A) 间接激活，从而促进血管生成。在这项研究中，我们发现生长停滞特异性蛋白 6 (Gas6)（Axl 的一种特异性配体）在 PDR 患者的玻璃体中升高，并且 Axl 在 PDR 患者的 FVM 中被激活。此外，我们证明，在培养的人视网膜微血管内皮细胞（HREC）中，通过使用成簇规则间隔短回文重复/CRISPR相关蛋白9抑制Axl表达或通过其特异性抑制剂R428失活来抑制Axl，可阻断PDR玻璃体诱导的Akt激活和HREC增殖。此外，PDR 玻璃体增强的 HREC 迁移和管形成也因抑制 Axl 而减弱。这些结果表明，在 PDR 的发病机制中，Axl 可以被 Gas6 直接结合激活，也可以通过细胞内途径被 VEGF-A 间接激活，这表明 Axl 在 PDR 的发生发展中发挥着关键作用，Axl 抑制为 PDR 治疗显示了光明的前景。
Proliferative diabetic retinopathy (PDR), characterized mainly with abnormal epiretinal angiogenesis forming fibrovascular membranes (FVMs), threatens vision of people with diabetes; FVMs consist of extracellular matrix and a variety of cell types including vascular endothelial cells. Axl, one of receptor tyrosine kinases, can be activated indirectly by vascular endothelial growth factor-A (VEGF-A) via an intracellular route for promoting angiogenesis. In this study, we revealed that growth arrest-specific protein 6 (Gas6), a specific ligand of Axl, was elevated in vitreous from patients with PDR and that Axl was activated in FVMs from patients with PDR. In addition, we demonstrated that in cultured human retinal microvascular endothelial cells (HRECs), Axl inhibition via suppression of Axl expression with Clustered Regularly Interspaced Short Palindromic Repeats/ CRISPR-associated protein 9 or through inactivation with its specific inhibitor R428 blocked PDR vitreous-induced Akt activation and proliferation of HRECs. Furthermore, PDR vitreous-heightened migration and tube formation of HRECs were also blunted by restraining Axl. These results indicate that in the pathogenesis of PDR, Axl can be activated by Gas6 binding directly and by VEGF-A via an intracellular route indirectly, suggesting that Axl plays a pivotal role in the development of PDR and that Axl inhibition shows a bright promise for PDR therapy.
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影响因子：
56.9
作者：
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通讯作者：
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