J Clin Invest. 2013 Nov;123(11):4900-8. doi: 10.1172/JCI70230.
Vascular networks develop from a growing vascular front that responds to VEGF and other guidance cues. Angiogenesis is required for normal tissue function, but, under conditions of stress, inappropriate vascularization can lead to disease. Therefore, inhibition of angiogenic sprouting may prevent neovascularization in patients with blinding neovascular eye diseases, including macular degeneration. VEGF antagonists have therapeutic benefits but also can elicit off-target effects. Here, we found that the Ras pathway, which functions downstream of a wide range of cytokines including VEGF, is active in the growing vascular front of developing and pathological vascular networks. The endogenous Ras inhibitor p120RasGAP was expressed predominately in quiescent VEGF-insensitive endothelial cells and was ectopically downregulated in multiple neovascular models. MicroRNA-132 negatively regulated p120RasGAP expression. Experimental delivery of α-miR-132 to developing mouse eyes disrupted tip cell Ras activity and prevented angiogenic sprouting. This strategy prevented ocular neovascularization in multiple rodent models even more potently than the VEGF antagonist, VEGF-trap. Targeting microRNA-132 as a therapeutic strategy may prove useful for treating multiple neovascular diseases of the eye and for preventing vision loss regardless of the neovascular stimulus.
血管网络从生长的血管前沿发育而来，该前沿对 VEGF 和其他导向线索做出反应。血管生成对于正常组织功能是必需的，但是，在应激条件下，不适当的血管生成可能导致疾病。因此，抑制血管生成发芽可能会预防患有致盲新生血管眼病（包括年龄相关性黄斑变性）的患者的新生血管形成。VEGF 拮抗剂具有治疗益处，但也可能引起非靶向作用。在这里，我们发现 Ras 途径在发育中和病理性血管网络的生长血管前沿中是活跃的，该途径在包括 VEGF 在内的广泛细胞因子的下游起作用。内源性 Ras 抑制剂 p120RasGAP 主要在静止的 VEGF 不敏感的内皮细胞中表达，并在多种新生血管模型中异位下调。microRNA-132 负调控 p120RasGAP 的表达。将α-miR-132 递送至发育中的小鼠眼睛中会破坏尖端细胞 Ras 活性并阻止血管生成发芽。与 VEGF 拮抗剂 VEGF-trap 相比，该策略甚至更有效地预防了多种啮齿动物模型中的眼部新生血管形成。将 microRNA-132 作为治疗策略可能有助于治疗多种眼部新生血管疾病，并防止视力丧失，而与新生血管刺激无关。
