title: Caveolin-1 modulates intraocular pressure: implications for caveolae mechanoprotection in glaucoma.
abstract: Polymorphisms in the CAV1/2 genes that encode signature proteins of caveolae are associated with glaucoma, the second leading cause of blindness worldwide, and with its major risk factor, intraocular pressure (IOP). We hypothesized that caveolin-1 (Cav-1) participates in IOP maintenance via modulation of aqueous humor drainage from the eye. We localize caveolae proteins to human and murine conventional drainage tissues and show that caveolae respond to mechanical stimulation. We show that Cav-1-deficient (Cav-1-/-) mice display ocular hypertension explained by reduced pressure-dependent drainage of aqueous humor. Cav-1 deficiency results in loss of caveolae in the Schlemm's canal (SC) and trabecular meshwork. However, their absence did not appear to impact development nor adult form of the conventional outflow tissues according to rigorous quantitative ultrastructural analyses, but did affect cell and tissue behavior. Thus, when IOP is experimentally elevated, cells of the Cav-1-/-outflow tissues are more susceptible to plasma membrane rupture indicating that caveolae play a role in mechanoprotection. Additionally, aqueous drainage from Cav-1-/-eyes was more sensitive to nitric oxide (NO) synthase inhibition than controls, suggesting that excess NO partially compensates for outflow pathway dysfunction. These results provide a functional link between a glaucoma risk gene and glaucoma-relevant pathophysiology.
authors.affiliation: Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, OK, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Elliott
authors.affiliation: Department of Ophthalmology/Duke Eye Center, Duke University, Durham, 27710, NC, USA.
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Ashpole
authors.affiliation: Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, OK, USA.
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Gu
authors.affiliation: Institute of Human Anatomy and Embryology, Universität Regensburg, 93053 Regensburg, Germany.
authors.forename: Leonie
authors.initials: L
authors.lastname: Herrnberger
authors.affiliation: Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, OK, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: McClellan
authors.affiliation: Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, OK, USA.
authors.forename: Gina L
authors.initials: GL
authors.lastname: Griffith
authors.affiliation: Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, OK, USA.
authors.forename: Alaina M
authors.initials: AM
authors.lastname: Reagan
authors.affiliation: Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, OK, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Boyce
authors.affiliation: Division of Ophthalmology, Matsue Red Cross Hospital, Matsue, Shimane 690-8506 Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Tanito
authors.affiliation: Institute of Human Anatomy and Embryology, Universität Regensburg, 93053 Regensburg, Germany.
authors.forename: Ernst R
authors.initials: ER
authors.lastname: Tamm
authors.affiliation: Department of Ophthalmology/Duke Eye Center, Duke University, Durham, 27710, NC, USA.
authors.forename: W Daniel
authors.initials: WD
authors.lastname: Stamer
mesh_terms: D000818:Animals; D021941:Caveolae / Q000378:metabolism* / Q000473:pathology; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D005901:Glaucoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007429:Intraocular Pressure; D051379:Mice; D018345:Mice, Knockout; D014129:Trabecular Meshwork / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
chemical_list: C495540:CAV1 protein, human; C495541:Cav1 protein, mouse; D051242:Caveolin 1