title: Loss of caveolin-1 causes blood-retinal barrier breakdown, venous enlargement, and mural cell alteration.
abstract: 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.
authors: 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.
authors: Xiaowu
authors: X
authors: Gu
authors: 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.
authors: Steven J
authors: SJ
authors: Fliesler
authors: Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois; Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois.
authors: You-Yang
authors: YY
authors: Zhao
authors: Tumor Microenvironment Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California.
authors: William B
authors: WB
authors: Stallcup
authors: 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.
authors: Alex W
authors: AW
authors: Cohen
authors: 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. Electronic address: michael-elliott@ouhsc.edu.
authors: Michael H
authors: MH
authors: Elliott
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001813:Blood-Retinal Barrier / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D051242:Caveolin 1 / Q000172:deficiency* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010539:Permeability; D010641:Phenotype; D021381:Protein Transport; D012169:Retinal Vein / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D062725:Tight Junction Proteins / Q000378:metabolism
chemical_list: D015415:Biomarkers; D051242:Caveolin 1; D062725:Tight Junction Proteins; D052250:Nitric Oxide Synthase Type III