Recombinant human VEGF165b inhibits experimental choroidal neovascularization.
OBJECTIVE
Vascular endothelial growth factor (VEGF-A) is the principal stimulator of angiogenesis in wet age-related macular degeneration (AMD). However, VEGF-A is generated by alternate splicing into two families, the proangiogenic VEGF-A(xxx) family and the antiangiogenic VEGF-A(xxx)b family. It is the proangiogenic family that is responsible for the blood vessel growth seen in AMD.


METHODS
To determine the role of antiangiogenic isoforms of VEGF-A as inhibitors of choroidal neovascularization, the authors used a model of laser-induced choroidal neovascularization in the mouse eye and investigated VEGF-A(165)b effects on endothelial cells and VEGFRs in vitro.


RESULTS
VEGF-A(165)b inhibited VEGF-A(165)-mediated endothelial cell migration with a dose effect similar to that of ranibizumab and bevacizumab and 200-fold more potent than that of pegaptanib. VEGF-A(165)b bound both VEGFR1 and VEGFR2 with affinity similar to that of VEGF-A(165). After laser injury, mice were injected either intraocularly or subcutaneously with recombinant human VEGF-A(165)b. Intraocular injection of rhVEGF-A(165)b gave a pronounced dose-dependent inhibition of fluorescein leakage, with an IC(50) of 16 pg/eye, neovascularization (IC(50), 0.8 pg/eye), and lesion as assessed by histologic staining (IC(50), 8 pg/eye). Subcutaneous administration of 100 microg twice a week also inhibited fluorescein leakage and neovascularization and reduced lesion size.


CONCLUSIONS
These results show that VEGF-A(165)b is a potent antiangiogenic agent in a mouse model of age-related macular degeneration and suggest that increasing the ratio of antiangiogenic-to-proangiogenic isoforms may be therapeutically effective in this condition.
Microvascular Research Laboratories, Department of Physiology and Pharmacology, Bristol Heart Institute, School of Veterinary Sciences, University of Bristol, Bristol, UK.
Jing
J
Hua
Christine
C
Spee
Satoru
S
Kase
Emma S
ES
Rennel
Anette L
AL
Magnussen
Yan
Y
Qiu
Alex
A
Varey
Sandeep
S
Dhayade
Amanda J
AJ
Churchill
Steven J
SJ
Harper
David O
DO
Bates
David R
DR
Hinton
D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D020256:Choroidal Neovascularization / Q000175:diagnosis / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005451:Fluorescein Angiography; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology; D012171:Retinal Vessels; D020349:Surface Plasmon Resonance; D042461:Vascular Endothelial Growth Factor A / Q000493:pharmacokinetics / Q000494:pharmacology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2