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.
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.
Aiello
L P
LP
Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Bursell
S E
SE
Clermont
A
A
Duh
E
E
Ishii
H
H
Takagi
C
C
Mori
F
F
Ciulla
T A
TA
Ways
K
K
Jirousek
M
M
Smith
L E
LE
King
G L
GL
D000818:Animals; D002199:Capillary Permeability; D002417:Cattle; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005123:Eye / Q000098:blood supply*; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology; D008222:Lymphokines / Q000502:physiology*; D008301:Maleimides / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D012160:Retina / Q000201:enzymology*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D008222:Lymphokines; D008301:Maleimides; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C099154:ruboxistaurin; D011493:Protein Kinase C