J Clin Invest. 2013 Oct;123(10):4170-81. doi: 10.1172/JCI67315. Epub 2013 Sep 9.
Neovascular age-related macular degeneration is a leading cause of irreversible vision loss in the Western world. Cytokine-targeted therapies (such as anti-vascular endothelial growth factor) are effective in treating pathologic ocular angiogenesis, but have not led to a durable effect and often require indefinite treatment. Here, we show that Nutlin-3, a small molecule antagonist of the E3 ubiquitin protein ligase MDM2, inhibited angiogenesis in several model systems. We found that a functional p53 pathway was essential for Nutlin-3-mediated retinal antiangiogenesis and disruption of the p53 transcriptional network abolished the antiangiogenic activity of Nutlin-3. Nutlin-3 did not inhibit established, mature blood vessels in the adult mouse retina, suggesting that only proliferating retinal vessels are sensitive to Nutlin-3. Furthermore, Nutlin-3 inhibited angiogenesis in nonretinal models such as the hind limb ischemia model. Our work demonstrates that Nutlin-3 functions through an antiproliferative pathway with conceivable advantages over existing cytokine-targeted antiangiogenesis therapies.
年龄相关性黄斑变性是西方世界导致不可逆视力丧失的主要原因。细胞因子靶向治疗（如抗血管内皮生长因子）在治疗病理性眼血管生成方面是有效的，但并没有产生持久的效果，而且往往需要无限期的治疗。在这里，我们表明，小分子 E3 泛素蛋白连接酶 MDM2 的拮抗剂 Nutlin-3 抑制了几种模型系统中的血管生成。我们发现，功能性 p53 途径对于 Nutlin-3 介导的视网膜抗血管生成是必不可少的，而 p53 转录网络的破坏则消除了 Nutlin-3 的抗血管生成活性。Nutlin-3 不会抑制成年小鼠视网膜中已建立的成熟血管，这表明只有增殖的视网膜血管对 Nutlin-3 敏感。此外，Nutlin-3 还抑制了后腿缺血模型等非视网膜模型中的血管生成。我们的工作表明，Nutlin-3 通过一种有丝分裂抑制途径发挥作用，与现有的细胞因子靶向抗血管生成治疗相比具有明显的优势。
