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D. M. Kleinman, D. D. Kim, T. Nivaggioli, T. Kanetaka, M. E. Gerritsen, D. A. Weber, W. N. Duran; Sirolimus Inhibits VEGF-Induced Microvascular Hyperpermeability. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1422.
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Sirolimus is a potent inhibitor of endothelial cell and fibroblast proliferation and is being developed for the treatment of exudative age-related macular degeneration and diabetic retinopathy. Sirolimus impacts multiple steps in the angiogenic cascade, including inhibition of endothelial cell responses to pro-angiogenic factors. However, it was not known whether sirolimus could inhibit hyperpermeability associated with angiogenesis and VEGF upregulation. As reductions in macular edema have been clinically-associated with rapid gains in vision, we investigated how sirolimus influences the microvasculature under conditions of VEGF-induced hyperpermeability.
The hamster cheek pouch was studied using intravital microscopy and computer assisted image analysis. Male golden Syrian hamsters (80-120g) were treated intraperitoneally with vehicle (negative control), caveolin-1 scaffolding (1 mg/kg; positive control), or sirolimus (at 0.1, 0.5, and 2.0 mg/kg) at 24 hours and one hour prior to preparation of the cheek pouch. VEGF (10-8 M) or PAF (10-7 M) was then topically applied to the cheek pouch. Microvascular permeability and arteriolar diameter were assessed using integrated optical intensity (IOI) and vascular wall imaging, respectively.
Sirolimus at either 0.1 mg/kg or 0.5 mg/kg significantly reduced VEGF-stimulated mean IOI from 63.0 ± 4.2 to 9.7 ± 5.0 (85% reduction, P<0.001) and 3.6 ± 2.7 (95% reduction, P<0.001), respectively. Sirolimus at 2 mg/kg also lowered VEGF-stimulated hyperpermeability (40% reduction, P<0.05). Sirolimus attenuated VEGF-induced vasodilation and PAF-induced hyperpermeability, but did not influence PAF-induced vasoconstriction.
Sirolimus inhibits VEGF-induced microvascular hyperpermeability. This inhibition is 1) a direct effect on the endothelial barrier, and 2) independent of vasodilation, a pre-capillary event. Sirolimus may be beneficial for patients suffering visual loss from diabetic macular edema or retinal thickening secondary to leakage associated with choroidal neovascular membranes.
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