Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor

• Published in: Diabetes (New York, N.Y.) Vol. 46; no. 9; pp. 1473 - 1480
• Main Authors: Aiello, L. P., Bursell, S. E., Clermont, A., Duh, E., Ishii, H., Takagi, C., Mori, F., Ciulla, T. A., Ways, K., Jirousek, M., Smith, L. E., King, G. L.
• Format: Journal Article
• Language: English
• Published: American Diabetes Association 01-09-1997
• ISSN: 0012-1797; 1939-327X; 0012-1797
• DOI: 10.2337/diabetes.46.9.1473

Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by
an orally effective beta-isoform-selective inhibitor.
L P Aiello ,
S E Bursell ,
A Clermont ,
E Duh ,
H Ishii ,
C Takagi ,
F Mori ,
T A Ciulla ,
K Ways ,
M Jirousek ,
L E Smith and
G L King
Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Abstract
Increased vascular permeability and excessive neovascularization 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 alpha, betaII, and delta and >threefold increases in
retinal vasopermeability in vivo. The effect of VEGF on retinal vascular permeability appears to be mediated predominantly
by the beta-isoform of PKC with >95% inhibition of VEGF-induced permeability by intravitreal or oral administration of a PKC
beta-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 beta-isoform-selective inhibitors may prove efficacious for the treatment of
VEGF-associated ocular disorders such as diabetic retinopathy.