Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Research Service, Veterans Affairs Western New York Healthcare System, Buffalo, New York; Department of Ophthalmology, University at Buffalo, State University of New York, Buffalo, New York; Department of Biochemistry, University at Buffalo, State University of New York, Buffalo, New York; SUNY Eye Institute, University at Buffalo, State University of New York, Buffalo, New York.
Am J Pathol. 2014 Feb;184(2):541-55. doi: 10.1016/j.ajpath.2013.10.022. Epub 2013 Dec 8.
Blood-retinal barrier (BRB) breakdown and related vascular changes are implicated in several ocular diseases. The molecules and mechanisms regulating BRB integrity and pathophysiology are not fully elucidated. Caveolin-1 (Cav-1) ablation results in loss of caveolae and microvascular pathologies, but the role of Cav-1 in the retina is largely unknown. We examined BRB integrity and vasculature in Cav-1 knockout mice and found a significant increase in BRB permeability, compared with wild-type controls, with branch veins being frequent sites of breakdown. Vascular hyperpermeability occurred without apparent alteration in junctional proteins. Such hyperpermeability was not rescued by inhibiting eNOS activity. Veins of Cav-1 knockout retinas exhibited additional pathological features, including i) eNOS-independent enlargement, ii) altered expression of mural cell markers (eg, down-regulation of NG2 and up-regulation of αSMA), and iii) dramatic alterations in mural cell phenotype near the optic nerve head. We observed a significant NO-dependent increase in retinal artery diameter in Cav-1 knockout mice, suggesting that Cav-1 plays a role in autoregulation of resistance vessels in the retina. These findings implicate Cav-1 in maintaining BRB integrity in retinal vasculature and suggest a previously undefined role in the retinal venous system and associated mural cells. Our results are relevant to clinically significant retinal disorders with vascular pathologies, including diabetic retinopathy, uveoretinitis, and primary open-angle glaucoma.
血视网膜屏障 (BRB) 的破坏和相关的血管变化与几种眼部疾病有关。调节 BRB 完整性和病理生理学的分子和机制尚未完全阐明。窖蛋白-1 (Cav-1) 的缺失会导致小窝和微血管病变，但 Cav-1 在视网膜中的作用在很大程度上尚不清楚。我们研究了 Cav-1 敲除小鼠的 BRB 完整性和血管，发现与野生型对照组相比，BRB 通透性显著增加，分支静脉是破坏的常见部位。血管通透性增加而连接蛋白没有明显改变。抑制 eNOS 活性并不能挽救这种高通透性。Cav-1 敲除视网膜的静脉表现出其他病理特征，包括 i）eNOS 非依赖性增大，ii）壁细胞标志物的表达改变（例如，NG2 下调和 αSMA 上调），以及 iii）视神经头部附近壁细胞表型的剧烈改变。我们观察到 Cav-1 敲除小鼠视网膜动脉直径有明显的依赖于 NO 的增加，表明 Cav-1 在视网膜阻力血管的自动调节中起作用。这些发现表明 Cav-1 在维持视网膜血管的 BRB 完整性方面发挥作用，并暗示其在视网膜静脉系统和相关壁细胞中具有以前未定义的作用。我们的研究结果与具有血管病变的临床显著视网膜疾病相关，包括糖尿病视网膜病变、葡萄膜炎和原发性开角型青光眼。
