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Alaina Reagan; LOSS OF CAVEOLIN-1 ALTERS ALPHA SMOOTH MUSCLE CELL COVERAGE ON RETINAL ARTERIES FOLLOWING ACUTE ISCHEMIC INSULT. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4603.
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© ARVO (1962-2015); The Authors (2016-present)
Caveolin-1, (Cav-1) the primary scaffolding protein of caveolae membrane domains, plays important roles in retinal vascular function, neuroprotection, and innate inflammatory signaling. Polymorphisms at the CAV1 locus are associated with primary open angle glaucoma. In the present study, we examine the effect of Cav-1 deficiency on retinal and vascular responses to ischemia-reperfusion (I/R) induced by acute intraocular pressure elevation.
The major risk factor for most types of glaucoma is elevated intraocular pressure (IOP). To create elevated IOP, Transient acute ischemia was induced in one eye of Cav-1 knockout (KO), endothelial-specific Cav-1 KO and and control mice via a 33-gauge anterior segment cannula connected to an elevated saline reservoir such that intraocular pressure was raised to 100 mmHg for 50 minutes and the needle was removed to allow for retinal reperfusion. Contralateral eyes were used as controls. 3 days post I/R, immunohistochemistry was performed on retinal flatmounts to assess vascular changes. 28 days post I/R, ganglion cell viability was determined using IHC.
Cav-1 KO retinal arteries show two-fold reduction in alpha smooth muscle actin (αSMA) immunoreactivity after I/R when compared to controls, demonstrating that loss of Cav-1 directly influences the arterial response to pressure. Specifically, ischemic Cav-1 KO mice show distinct focal segmental loss of αSMA, both near the optic nerve and peripherally. Experiments were repeated in endothelial-specific KO mice, and no significant reduction in αSMA was observed, indicating that endothelial Cav-1 and endothelium-derived factors like nitric oxide are not contributing to the phenotype. Ganglion cell death occurred in both control and Cav-1 KO animals following I/R. Surprisingly, cell death within WT retinas was substantially greater than in the Cav-1 KO retinas, indicating that loss of Cav-1 may provide specific neuronal protection.
These data provide a novel role for Cav-1 as a regulator of resistance vessel contractile properties in the post-ischemic retina. Because loss of αSMA increases arterial diameter, increased blood flow to the KO retina might provide crucial nutrients to injured neurons. Experiments will be repeated in neural retina-specific KO as well as smooth muscle cell-specific KO animals to narrow down the cell type responsible for the arterial phenotype.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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