May 2007
Volume 48, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2007
Sirolimus Inhibits VEGF-Induced Microvascular Hyperpermeability
Author Affiliations & Notes
  • D. M. Kleinman
    University of Rochester Eye Institute, Rochester, New York
  • D. D. Kim
    Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, Newark, New Jersey
  • T. Nivaggioli
    MacuSight, Inc., Union City, California
  • T. Kanetaka
    Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, Newark, New Jersey
  • M. E. Gerritsen
    MacuSight, Inc., Union City, California
  • D. A. Weber
    MacuSight, Inc., Union City, California
  • W. N. Duran
    Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, Newark, New Jersey
  • Footnotes
    Commercial Relationships D.M. Kleinman, MacuSight, Inc., I; MacuSight, Inc., Bausch and Lomb, Inc., C; MacuSight, Inc., P; D.D. Kim, MacuSight, Inc., F; T. Nivaggioli, MacuSight, Inc., E; MacuSight, Inc., P; T. Kanetaka, MacuSight, Inc., F; M.E. Gerritsen, MacuSight, Inc., C; MacuSight, Inc., P; D.A. Weber, MacuSight, Inc., I; MacuSight, Inc., E; MacuSight, Inc., P; W.N. Duran, MacuSight, Inc., F.
  • Footnotes
    Support None.
Investigative Ophthalmology & Visual Science May 2007, Vol.48, 1422. doi:
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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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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose:: 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.

Methods:: 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.

Results:: 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.

Conclusions:: 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.

Keywords: age-related macular degeneration • diabetic retinopathy • retina 
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