SCF (Stem Cell Factor) and cKIT Modulate Pathological Ocular Neovascularization
SCF (Stem Cell Factor) and cKIT Modulate Pathological Ocular Neovascularization
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DOI：
10.1161/atvbaha.119.313179
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发表时间：
2019-10-01
影响因子：
8.7
通讯作者：
Suh, Wonhee
中科院分区：
文献类型：
--
作者：
Kim, Koung Li;Seo, Songyi;Suh, Wonhee
目的：异常新生血管形成是几种眼部疾病中失明的主要原因，包括年龄相关性黄斑变性和增殖性糖尿病视网膜病变。病理性眼部新生血管形成的关键调节因子的鉴定一直是广泛研究和巨大治疗兴趣的主题。在这里，我们探讨了以前未被认识到的cKIT及其配体，SCF（干细胞因子），在病理性眼部新生血管形成过程中的作用。方法和结果：与常氧相比，缺氧，新血管形成的关键驱动因素，导致cKIT在内皮细胞中高度上调，这显著增强了内皮细胞对SCF的血管生成反应。在病理性眼部新生血管形成的小鼠模型中，例如氧诱导的视网膜病变和激光诱导的脉络膜新生血管形成模型，cKIT和SCF表达在眼部组织中显著增加，并且使用cKit突变小鼠和抗SCF中和IgG阻断cKIT和SCF基本上抑制了病理性眼部新生血管形成。SCF/cKIT信号通过糖原合成酶激酶-3 β的磷酸化和β-连环蛋白核转位的增强以及与血管生成相关的β-连环蛋白靶基因的转录诱导新生血管形成。使用化学抑制剂抑制β-连环蛋白介导的转录阻断了缺氧条件下SCF诱导的体外血管生成，将β-连环蛋白激动剂注射到患有氧诱导视网膜病变的cKit突变小鼠中显著增强了视网膜中的病理性新生血管形成。结论：我们的数据显示SCF和cKIT是治疗威胁视力的眼部新生血管性疾病的有前途的新治疗靶点。
Objective: Aberrant neovascularization is a leading cause of blindness in several eye diseases, including age-related macular degeneration and proliferative diabetic retinopathy. The identification of key regulators of pathological ocular neovascularization has been a subject of extensive research and great therapeutic interest. Here, we explored the previously unrecognized role of cKIT and its ligand, SCF (stem cell factor), in the pathological ocular neovascularization process. Approach and Results: Compared with normoxia, hypoxia, a crucial driver of neovascularization, caused cKIT to be highly upregulated in endothelial cells, which significantly enhanced the angiogenic response of endothelial cells to SCF. In murine models of pathological ocular neovascularization, such as oxygen-induced retinopathy and laser-induced choroidal neovascularization models, cKIT and SCF expression was significantly increased in ocular tissues, and blockade of cKIT and SCF using cKit mutant mice and anti-SCF neutralizing IgG substantially suppressed pathological ocular neovascularization. Mechanistically, SCF/cKIT signaling induced neovascularization through phosphorylation of glycogen synthase kinase-3 beta and enhancement of the nuclear translocation of beta-catenin and the transcription of beta-catenin target genes related to angiogenesis. Inhibition of beta-catenin-mediated transcription using chemical inhibitors blocked SCF-induced in vitro angiogenesis in hypoxia, and injection of a beta-catenin agonist into cKit mutant mice with oxygen-induced retinopathy significantly enhanced pathological neovascularization in the retina. Conclusions; Our data reveal that SCF and cKIT are promising novel therapeutic targets for treating vision-threatening ocular neovascular diseases.