Prolonged blockade of VEGF family members does not cause identifiable damage to retinal neurons or vessels.
Several ocular diseases complicated by neovascularization are being treated by repeated intraocular injections of vascular endothelial growth factor (VEGF) antagonists. While substantial benefits have been documented, there is concern that unrecognized damage may be occurring, because blockade of VEGF may damage the fenestrated vessels of the choroicapillaris and deprive retinal neurons of input from a survival factor. One report has suggested that even temporary blockade of all isoforms of VEGF-A results in significant loss of retinal ganglion cells. In this study, we utilized double transgenic mice with doxycycline-inducible expression of soluble VEGF receptor 1 coupled to an Fc fragment (sVEGFR1Fc), a potent antagonist of several VEGF family members, including VEGF-A, to test the effects of VEGF blockade in the retina. Expression of sVEGFR1Fc completely blocked VEGF-induced retinal vascular permeability and significantly suppressed the development of choroidal neovascularization at rupture sites in Bruch's membrane, but did not cause regression of established choroidal neovascularization. Mice with constant expression of sVEGFR1Fc in the retina for 7 months had normal electroretinograms and normal retinal and choroidal ultrastructure including normal fenestrations in the choroicapillaris. They also showed no significant difference from control mice in the number of ganglion cell axons in optic nerve cross sections and the retinal level of mRNA for 3 ganglion cell-specific genes. These data indicate that constant blockade of VEGF for up to 7 months has no identifiable deleterious effects on the retina or choroid and support the use of VEGF antagonists in the treatment of retinal diseases.
Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Shinji
S
Ueno
Mary Ellen
ME
Pease
Delphine M Bonnet
DM
Wersinger
Tomohiro
T
Masuda
Stanley A
SA
Vinores
Tamar
T
Licht
Donald J
DJ
Zack
Harry
H
Quigley
Eli
E
Keshet
Peter A
PA
Campochiaro
D000818:Animals; D017209:Apoptosis; D020256:Choroidal Neovascularization; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D018919:Neovascularization, Physiologic; D012333:RNA, Messenger / Q000032:analysis; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000648:ultrastructure*; D015861:Retinal Neovascularization; D012171:Retinal Vessels / Q000378:metabolism / Q000648:ultrastructure*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A