Plasma Kallikrein Mediates Vascular Endothelial Growth Factor-Induced Retinal Dysfunction and Thickening.
Plasma Kallikrein Mediates Vascular Endothelial Growth Factor-Induced Retinal Dysfunction and Thickening.
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DOI：
10.1167/iovs.15-18272
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发表时间：
2016-05-01
影响因子：
4.4
通讯作者：
Feener EP
中科院分区：
文献类型：
--
作者：
Clermont A;Murugesan N;Zhou Q;Kita T;Robson PA;Rushbrooke LJ;Evans DM;Aiello LP;Feener EP
血浆激肽释放酶是一种丝氨酸蛋白酶和炎症的循环组分，其对血管源性水肿产生临床显著影响。本研究探讨血浆激肽释放酶在VEGF诱导的视网膜水肿中的作用。在血浆前激肽释放酶缺陷型（KLKB 1-/-）和野生型（WT）小鼠以及接受选择性血浆激肽释放酶抑制剂VA999272的大鼠和小鼠中进行VEGF和生理盐水溶剂的玻璃体内注射。用伊文思蓝渗透法和光学相干断层扫描法分别测量视网膜血管通透性（RVP）和视网膜厚度。采用免疫印迹法和免疫组化法检测视网膜激肽释放酶激肽系统。在经历氧诱导视网膜病变的KLKB 1 −/−和WT小鼠中研究视网膜新生血管形成。与WT小鼠中的VEGF反应相比，KLKB 1 −/−小鼠中血管内皮生长因子诱导的RVP和视网膜增厚分别减少了68%和47%。血浆激肽释放酶也有助于TNF α诱导的视网膜增厚，在KLKB 1 −/−小鼠中减少了52%。与载体处理的对照组相比，VA 999272的全身给药使VEGF诱导的视网膜增厚在小鼠中减少57%（P <0.001），在大鼠中减少53%（P <0.001）。在WT小鼠中玻璃体内注射VEGF增加了视网膜中的血浆前激肽释放酶，其弥漫性分布在整个视网膜内层和外层。在WT和KLKB 1 −/−小鼠中，由氧诱导的视网膜病变诱导的无血管和新生血管区域相似。血管内皮生长因子增加血浆激肽释放酶外渗到视网膜中，并且血浆激肽释放酶是VEGF对啮齿动物中的RVP和视网膜增厚的全部作用所必需的。全身性血浆激肽释放酶抑制可提供治疗VEGF诱导的视网膜水肿的治疗机会。
Plasma kallikrein is a serine protease and circulating component of inflammation, which exerts clinically significant effects on vasogenic edema. This study examines the role of plasma kallikrein in VEGF-induced retinal edema. Intravitreal injections of VEGF and saline vehicle were performed in plasma prekallikrein–deficient (KLKB1−/−) and wild-type (WT) mice, and in both rats and mice receiving a selective plasma kallikrein inhibitor, VA999272. Retinal vascular permeability (RVP) and retinal thickness were measured by Evans blue permeation and optical coherence tomography, respectively. The retinal kallikrein kinin system was examined by Western blotting and immunohistochemistry. Retinal neovascularization was investigated in KLKB1−/− and WT mice subjected to oxygen-induced retinopathy. Vascular endothelial growth factor–induced RVP and retinal thickening were reduced in KLKB1−/− mice by 68% and 47%, respectively, compared to VEGF responses in WT mice. Plasma kallikrein also contributes to TNFα-induced retinal thickening, which was reduced by 52% in KLKB1−/− mice. Systemic administration of VA999272 reduced VEGF-induced retinal thickening by 57% (P < 0.001) in mice and 53% (P < 0.001) in rats, compared to vehicle-treated controls. Intravitreal injection of VEGF in WT mice increased plasma prekallikrein in the retina, which was diffusely distributed throughout the inner and outer retinal layers. Avascular and neovascular areas induced by oxygen-induced retinopathy were similar in WT and KLKB1−/− mice. Vascular endothelial growth factor increases extravasation of plasma kallikrein into the retina, and plasma kallikrein is required for the full effects of VEGF on RVP and retinal thickening in rodents. Systemic plasma kallikrein inhibition may provide a therapeutic opportunity to treat VEGF-induced retina edema.