title: Astrocyte Structural and Molecular Response to Elevated Intraocular Pressure Occurs Rapidly and Precedes Axonal Tubulin Rearrangement within the Optic Nerve Head in a Rat Model.
abstract: Glaucomatous axon injury occurs at the level of the optic nerve head (ONH) in response to uncontrolled intraocular pressure (IOP). The temporal response of ONH astrocytes (glial cells responsible for axonal support) to elevated IOP remains unknown. Here, we evaluate the response of actin-based astrocyte extensions and integrin-based signaling within the ONH to 8 hours of IOP elevation in a rat model. IOP elevation of 60 mm Hg was achieved under isoflurane anesthesia using anterior chamber cannulation connected to a saline reservoir. ONH astrocytic extension orientation was significantly and regionally rearranged immediately after IOP elevation (inferior ONH, 43.2° ± 13.3° with respect to the anterior-posterior axis versus 84.1° ± 1.3° in controls, p<0.05), and re-orientated back to baseline orientation 1 day post IOP normalization. ONH axonal microtubule filament label intensity was significantly reduced 1 and 3 days post IOP normalization, and returned to control levels on day 5. Phosphorylated focal adhesion kinase (FAK) levels steadily decreased after IOP normalization, while levels of phosphorylated paxillin (a downstream target of FAK involved in focal adhesion dynamics) were significantly elevated 5 days post IOP normalization. The levels of phosphorylated cortactin (a downstream target of Src kinase involved in actin polymerization) were significantly elevated 1 and 3 days post IOP normalization and returned to control levels by day 5. No significant axon degeneration was noted by morphologic assessment up to 5 days post IOP normalization. Actin-based astrocyte structure and signaling within the ONH are significantly altered within hours after IOP elevation and prior to axonal cytoskeletal rearrangement, producing some responses that recover rapidly and others that persist for days despite IOP normalization.
authors.affiliation: Casey Eye Institute, Department of Ophthalmology, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Shandiz
authors.initials: S
authors.lastname: Tehrani
authors.affiliation: Casey Eye Institute, Department of Ophthalmology, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Lauren
authors.initials: L
authors.lastname: Davis
authors.affiliation: Casey Eye Institute, Department of Ophthalmology, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: William O
authors.initials: WO
authors.lastname: Cepurna
authors.affiliation: Casey Eye Institute, Department of Ophthalmology, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Tiffany E
authors.initials: TE
authors.lastname: Choe
authors.affiliation: Casey Eye Institute, Department of Ophthalmology, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Diana C
authors.initials: DC
authors.lastname: Lozano
authors.affiliation: Casey Eye Institute, Department of Ophthalmology, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Ashley
authors.initials: A
authors.lastname: Monfared
authors.affiliation: Casey Eye Institute, Department of Ophthalmology, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Lauren
authors.initials: L
authors.lastname: Cooper
authors.affiliation: Casey Eye Institute, Department of Ophthalmology, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Joshua
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Casey Eye Institute, Department of Ophthalmology, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Johnson
authors.affiliation: Casey Eye Institute, Department of Ophthalmology, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: John C
authors.initials: JC
authors.lastname: Morrison
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D001370:Axonal Transport; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D007429:Intraocular Pressure; D008297:Male; D009798:Ocular Hypertension / Q000378:metabolism / Q000473:pathology*; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D011914:Rats, Inbred BN; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000199:Actins; D014404:Tubulin