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Xiaowu Gu, Steven Fliesler, Michael Elliott; Loss of Caveolin-1 Results in Blood-Retinal Barrier Permeability, Venous Enlargement and Mural Cell Alteration. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5610.
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© ARVO (1962-2015); The Authors (2016-present)
Caveolin-1 (Cav-1) is the signature protein of caveolae and is intrinsically involved in lipid trafficking, transcytosis, and signal transduction. Cav-1 ablation results in loss of caveolae and in microvascular pathologies. Yet, the role of Cav-1 in maintaining blood-retinal barrier (BRB) integrity is unknown. Here, we determined the consequence of Cav-1 ablation on retinal vascular structure and function.
BRB integrity in Cav-1 single knockout (SKO) and wild-type (WT) mice was assessed by dextran permeability assay and albumin immunohistochemistry. Retinal vascular morphology, vessel diameters and mural cell coverage were assessed in retinal flatmounts stained for a variety of endothelial (CD31, ZO-1, claudin-5 and VE-cadherin) and mural cell markers (PDGFRβ, α-SMA and NG2). Tight junction integrity was visualized by HRP tracing using transmission electron microscopy (TEM). Retinas from Cav-1/endothelial nitric oxide synthase (eNOS) double knockout (DKO) mice also were examined.
Compared to WT, SKO mice displayed significant BRB breakdown (p=0.0017) and extravasation of endogenous serum albumin. Retinal veins were significantly enlarged in SKO mice (p<0.0001) and were not normalized to WT diameter in DKO retinas (DKO vs. WT p=0.0028, DKO vs. SKO p=0.1096). Reduced immunofluorescence signal intensity of the junctional proteins ZO-1 and claudin-5 was observed in SKO and DKO eyes, vs. WT, yet both proteins were properly localized to the endothelial borders. TEM, however, showed intact tight junctions in SKO retinal vasculature. The enlarged veins in SKO retinas, surprisingly, were deficient in NG2 immunoreactivity, yet PDGFRβ and α-SMA immunostaining was comparable to WT.
Our results suggest that Cav-1 plays an important role in the maintenance of inner BRB integrity through a novel mechanism that may involve mural cell/endothelium interactions. This may have relevance to retinal vascular pathologies where changes in Cav-1 expression have been implicated.
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