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Original Articles

Vascular Endothelial Growth Factor–Induced Retinal Permeability Is Mediated by Protein Kinase C In Vivo and Suppressed by an Orally Effective β-Isoform–Selective Inhibitor

  1. Lloyd Paul Aiello,
  2. Sven-Erik Bursell,
  3. Allen Clermont,
  4. Elia Duh,
  5. Hidehiro Ishii,
  6. Chikako Takagi,
  7. Fumi Mori,
  8. Thomas A Ciulla,
  9. Kirk Ways,
  10. Michael Jirousek,
  11. Lois E H Smith and
  12. George L King
  1. Research Division, Harvard Medical School Indianapolis, Indiana
  2. Beetham Eye Institute, Joslin Diabetes Center, Harvard Medical School Indianapolis, Indiana
  3. Department of Ophthalmology, Harvard Medical School Indianapolis, Indiana
  4. Department of Ophthalmology, Children's Hospital Boston, Massachusetts
  5. Department of Medicine, Brigham & Women's Hospital Boston, Massachusetts
  6. Department of Ophthalmology, Indiana University Indianapolis, Indiana
  7. Lilly Research Laboratories Indianapolis, Indiana
  1. Address correspondence and reprint requests to George L. King, MD, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail: kinggl{at}joslab.harvard.edu.
Diabetes 1997 Sep; 46(9): 1473-1480. https://doi.org/10.2337/diab.46.9.1473
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Abstract

Increased vascular permeability and excessive neovas-cularization are the hallmarks of endothelial dysfunction, which can lead to diabetic macular edema and proliferative diabetic retinopathy in the eye. Vascular endothelial growth factor (VEGF) is an important mediator of ocular neovascularization and a known vasopermeability factor in nonocular tissues. In these studies, we demonstrate that intravitreal injection of VEGF rapidly activates protein kinase C (PKC) in the retina at concentrations observed clinically, inducing membrane translocation of PKC isoforms α, βII, and δ and > threefold increases in retinal vasopermeability in vivo. The effect of VEGF on retinal vascular permeability appears to be mediated predominantly by the β-isoform of PKC with >95% inhibition of VEGF-induced permeability by intravitreal or oral administration of a PKC β-isoform-selective inhibitor that did not inhibit histamine-mediated effects. These studies represent the first direct demonstration that VEGF can increase intraocular vascular permeability through activation of PKC in vivo and suggest that oral pharmacological therapies involving PKC β-isoform-selective inhibitors may prove efficacious for the treatment of VEGF-asso-ciated ocular disorders such as diabetic retinopathy.

  • Received April 14, 1997.
  • Revision received May 12, 1997.
  • Accepted May 12, 1997.
  • Copyright © 1997 by the American Diabetes Association

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September 1997, 46(9)
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Vascular Endothelial Growth Factor–Induced Retinal Permeability Is Mediated by Protein Kinase C In Vivo and Suppressed by an Orally Effective β-Isoform–Selective Inhibitor
Lloyd Paul Aiello, Sven-Erik Bursell, Allen Clermont, Elia Duh, Hidehiro Ishii, Chikako Takagi, Fumi Mori, Thomas A Ciulla, Kirk Ways, Michael Jirousek, Lois E H Smith, George L King
Diabetes Sep 1997, 46 (9) 1473-1480; DOI: 10.2337/diab.46.9.1473

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Vascular Endothelial Growth Factor–Induced Retinal Permeability Is Mediated by Protein Kinase C In Vivo and Suppressed by an Orally Effective β-Isoform–Selective Inhibitor
Lloyd Paul Aiello, Sven-Erik Bursell, Allen Clermont, Elia Duh, Hidehiro Ishii, Chikako Takagi, Fumi Mori, Thomas A Ciulla, Kirk Ways, Michael Jirousek, Lois E H Smith, George L King
Diabetes Sep 1997, 46 (9) 1473-1480; DOI: 10.2337/diab.46.9.1473
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