Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature
Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature
复制标题
DOI：
10.1172/jci74527
复制
发表时间：
2014-10-01
影响因子：
15.9
通讯作者：
Campochiaro, Peter A.
中科院分区：
文献类型：
--
作者：
Shen, Jikui;Frye, Maike;Campochiaro, Peter A.
视网膜和脉络膜新生血管（NV）和血管渗漏导致几种常见眼部疾病的视力损害。血管生成素/TIE 2（ANG/TIE 2）通路维持血管完整性，该通路的负调节因子是这些疾病的潜在治疗靶点。在这里，我们证明了血管内皮蛋白酪氨酸磷酸酶（VE-PTP），负调节TIE 2的激活，是在缺氧血管内皮细胞，特别是在视网膜NV上调。眼内注射先前显示激活TIE 2的抗VE-PTP抗体抑制眼NV。此外，VE-PTP催化活性的小分子抑制剂（AKB-9778）激活TIE 2，增强ANG 1诱导的TIE 2激活，并刺激TIE 2通路中信号分子的磷酸化，包括AKT，eNOS和ERK。在新生血管性年龄相关性黄斑变性小鼠模型中，AKB-9778诱导TIE 2磷酸化并强烈抑制NV。缺血诱导的视网膜NV与糖尿病视网膜病变相关，通过ANG 2的诱导而加重，但即使在高水平ANG 2存在下，AKB-9778也能抑制。AKB-9778还可以阻断VEGF诱导的真皮和视网膜血管渗漏，并预防光感受器中VEGF高表达的双转基因小鼠的渗出性视网膜脱离。这些数据支持靶向VE-PTP以稳定视网膜和脉络膜血管，并表明该策略对患有各种视网膜和脉络膜血管疾病的患者具有潜力
Retinal and choroidal neovascularization (NV) and vascular leakage contribute to visual impairment in several common ocular diseases. The angiopoietin/TIE2 (ANG/TIE2) pathway maintains vascular integrity, and negative regulators of this pathway are potential therapeutic targets for these diseases. Here, we demonstrated that vascular endothelial-protein tyrosine phosphatase (VE-PTP), which negatively regulates TIE2 activation, is upregulated in hypoxic vascular endothelial cells, particularly in retinal NV. Intraocular injection of an anti-VE-PTP antibody previously shown to activate TIE2 suppressed ocular NV. Furthermore, a small-molecule inhibitor of VE-PTP catalytic activity (AKB-9778) activated TIE2, enhanced,ANG1-induced TIE2 activation, and stimulated phosphorylation of signaling molecules in the TIE2 pathway, including AKT, eNOS, and ERK In mouse models of neovascular age-related macular degeneration, AKB-9778 induced phosphorylation of TIE2 and strongly suppressed NV. lschemia-induced retinal NV, which is relevant to diabetic retinopathy, was accentuated by the induction of ANG2 but inhibited by AKB-9778, even in the presence of high levels of ANG2. AKB-9778 also blocked VEGF-induced leakage from dermal and retinal vessels and prevented exudative retinal detachments in double-transgenic mice with high expression of VEGF in photoreceptors. These data support targeting VE-PTP to stabilize retinal and choroidal blood vessels and suggest that this strategy has potential for patients with a wide variety of retinal and choroidal vascular diseases