VEGF165b, an endogenous C-terminal splice variant of VEGF, inhibits retinal neovascularization in mice.
OBJECTIVE
Hypoxia driven ocular angiogenesis occurs in a range of ischemic retinopathies including proliferative diabetic retinopathy and retinopathy of prematurity. These conditions are initiated and sustained by hypoxia dependent vascular endothelial growth factor (VEGF) expression in the eye. There are two families of VEGF isoforms formed by differential splicing, the pro-angiogenic VEGF family, known to contribute to ocular neovascularization, and the anti-angiogenic VEGF family, which are downregulated in diabetic retinopathy in humans. The first member of the VEGF family to be isolated was VEGF165b. To determine whether VEGF165b could inhibit hypoxia driven angiogenesis in the eye, the oxygen induced retinopathy mouse model of ocular neovascularization was used.


METHODS
1 ng of recombinant human VEGF165b peptide was injected intraocularly upon return to normoxia after 5 days exposure to 95% oxygen, and neovascularization assessed.


RESULTS
VEGF165b significantly inhibited the percentage area of retinal neovascularization from 23+/-3% to 12+/-3.3%, and significantly increased normal vascular areas from 62+/-4% to 74+/-4%. The percentage area of residual ischemic retina was not affected.


CONCLUSIONS
These results show that a single injection of VEGF165b can significantly reduce preretinal neovascularization without inhibition of physiological intraretinal angiogenesis. Controlling the balance of VEGF(xxx) to VEGF(xxx) isoforms may therefore be therapeutically valuable in the treatment of proliferative eye diseases such as diabetic retinopathy and age related macular degeneration. The regulation of splicing between these two families of isoforms may provide a novel therapeutic strategy for proliferative eye disease.
Konopatskaya
O
O
Microvascular Research Laboratories, Preclinical Veterinary School, Department of Physiology, University of Bristol, Bristol, UK.
Churchill
A J
AJ
Harper
S J
SJ
Bates
David O
DO
Gardiner
T A
TA
D000818:Animals; D000831:Animals, Newborn; D004274:DNA, Recombinant; D014644:Genetic Variation; D006801:Humans; D000860:Hypoxia / Q000150:complications; D007267:Injections; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D012160:Retina / Q000473:pathology; D015861:Retinal Neovascularization / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D012171:Retinal Vessels / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000235:genetics* / Q000494:pharmacology*
D004274:DNA, Recombinant; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A