State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, People's Republic of China.
Center for Medical and Pharmaceutical Research, Binzhou Medical University, Yantai, Shandong 264003, People's Republic of China.
Proc Natl Acad Sci U S A. 2017 Oct 3;114(40):10737-10742. doi: 10.1073/pnas.1706394114. Epub 2017 Sep 18.
Ocular neovascularization is a devastating pathology of numerous ocular diseases and is a major cause of blindness. Caveolin-1 (Cav-1) plays important roles in the vascular system. However, little is known regarding its function and mechanisms in ocular neovascularization. Here, using comprehensive model systems and a cell permeable peptide of Cav-1, cavtratin, we show that Cav-1 is a critical player in ocular neovascularization. The genetic deletion of Cav-1 exacerbated and cavtratin administration inhibited choroidal and retinal neovascularization. Importantly, combined administration of cavtratin and anti-VEGF-A inhibited neovascularization more effectively than monotherapy, suggesting the existence of other pathways inhibited by cavtratin in addition to VEGF-A. Indeed, we found that cavtratin suppressed multiple critical components of pathological angiogenesis, including inflammation, permeability, PDGF-B and endothelial nitric oxide synthase expression (eNOS). Mechanistically, we show that cavtratin inhibits CNV and the survival and migration of microglia and macrophages via JNK. Together, our data demonstrate the unique advantages of cavtratin in antiangiogenic therapy to treat neovascular diseases.
眼内新生血管是多种眼病的破坏性病理，是失明的主要原因。小窝蛋白-1（Cav-1）在血管系统中发挥重要作用。然而，关于其在眼内新生血管中的功能和机制知之甚少。在这里，我们使用综合模型系统和 Cav-1 的细胞通透性肽 cavtratin，表明 Cav-1 是眼内新生血管形成的关键参与者。Cav-1 的基因缺失加剧了，而 cavtratin 的给药抑制脉络膜和视网膜新生血管形成。重要的是，cavtratin 与抗 VEGF-A 的联合给药比单独治疗更有效地抑制新生血管形成，这表明除了 VEGF-A 之外，cavtratin 还抑制其他途径。事实上，我们发现 cavtratin 抑制了病理性血管生成的多个关键成分，包括炎症、通透性、PDGF-B 和内皮型一氧化氮合酶表达（eNOS）。在机制上，我们表明 cavtratin 通过 JNK 抑制脉络膜新生血管形成以及小胶质细胞和巨噬细胞的存活和迁移。总之，我们的数据表明 cavtratin 在治疗新生血管疾病的抗血管生成治疗中具有独特的优势。
