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Xiaowu Gu, Steven J Fliesler, You-Yang Zhao, William B Stallcup, Alex Cohen, Michael H Elliott; A critical role for caveolin-1 in eNOS-dependent retinal arterial autoregulation and eNOS-independent retinal venous pathology. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6343.
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© ARVO (1962-2015); The Authors (2016-present)
Caveolin-1 (Cav-1) is the primary scaffold protein of caveolae, changes in which have been implicated in preclinical models of diabetic retinopathy and retinal degeneration. Recent GWAS has linked CAV1/2 polymorphisms to the risk of primary open angle glaucoma. Cav-1 is expressed in retinal endothelial cells, mural cells and Müller glia, which collectively comprise the inner blood-retinal barrier. The biological impact of Cav-1 loss to the retinal vasculature is unclear. Here we carefully examined branch retinal veins (BRVs) in a mouse Cav-1 knockout (SKO) model.
Retinal vascular morphology, vessel diameter, and mural cell coverage were assessed by immunohistochemistry, using retinal flatmounts from wildtype (WT) and SKO mice and a battery of endothelial (CD31) and mural cell markers (PDGFRβ, αSMA and NG2). To assess eNOS-dependent transient actions, L-NAME (a NOS inhibitor) was injected into WT and SKO mice. Cav-1/eNOS double KO (DKO) mice were used to evaluate long-term eNOS-dependent actions. To quantify mural cell numbers, SKO mice were crossed with mice expressing GFP driven by αSMA promoter to generate GFP/SKO and GFP/WT mice, and GFP-positive mural cells on the BRVs were compared.
Compared to WT, BRVs in SKO mice were significantly enlarged and were not normalized to WT level in DKO retinas nor in Cav-1 KO mice treated with L-NAME. Arteries were dilated in SKO retinas compared to WT. However, arterial dilation in SKO was corrected after L-NAME treatment, suggesting the venous enlargement is eNOS-independent, whereas artery diameter is eNOS-dependent. Mural cells on the enlarged BRVs in SKO had geographically-defined changes: close to the periphery, NG2 level was significantly decreased, while αSMA expression was concomitantly increased; conversely, close to optic nerve head, mural cells displayed “spindly” morphology with numerous disorganized processes. GFP positive cell numbers were comparable in BRVs of SKO and WT mice, indicating that decreased NG2 expression was not due to mural cell dropout.
Our results suggest that Cav-1 plays an important role in venous mural cell and is likely involved in mural cell/endothelium interactions. These Cav-1-dependent changes in mural cell morphology close to the optic nerve head are consistent with GWAS linkage of CAV1/2 polymorphisms with the risk of primary open angle glaucoma.
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