VEGF-A165b Is Cytoprotective and Antiangiogenic in the Retina

被引:67
作者
Magnussen, Anette L. [1 ]
Rennel, Emma S. [1 ]
Hua, Jing [1 ]
Bevan, Heather S. [1 ]
Beazley Long, Nicholas [1 ]
Lehrling, Christina [2 ]
Gammons, Melissa [1 ]
Floege, Juergen [3 ]
Harper, Steven J. [1 ]
Agostini, Hansjuergen T. [2 ]
Bates, David O. [1 ]
Churchill, Amanda J. [4 ]
机构
[1] Univ Bristol, Sch Vet Sci, Dept Physiol & Pharmacol, Microvasc Res Labs,Bristol Heart Inst, Bristol BS2 8EJ, Avon, England
[2] Univ Freiburg, Univ Eye Hosp, Freiburg, Germany
[3] Rhein Westfal TH Aachen, Univ Hosp, Div Nephrol & Clin Immunol, Achen, Germany
[4] Univ Bristol, Bristol Eye Hosp, Unit Ophthalmol, Bristol BS1 2LX, Avon, England
基金
英国惠康基金;
关键词
ENDOTHELIAL GROWTH-FACTOR; SPLICE VARIANT; DIABETIC-RETINOPATHY; ANGIOGENIC ISOFORMS; TUMOR-GROWTH; VEGF; VEGF(165)B; BEVACIZUMAB; CELLS; NEOVASCULARIZATION;
D O I
10.1167/iovs.09-4296
中图分类号
R77 [眼科学];
学科分类号
100212 ;
摘要
PURPOSE. A number of key ocular diseases, including diabetic retinopathy and age-related macular degeneration, are characterized by localized areas of epithelial or endothelial damage, which can ultimately result in the growth of fragile new blood vessels, vitreous hemorrhage, and retinal detachment. VEGF-A(165), the principal neovascular agent in ocular angiogenic conditions, is formed by proximal splice site selection in its terminal exon 8. Alternative splicing of this exon results in an antiangiogenic isoform, VEGF-A(165)b, which is downregulated in diabetic retinopathy. Here the authors investigate the antiangiogenic activity of VEGF(165)b and its effect on retinal epithelial and endothelial cell survival. METHODS. VEGF-A(165)b was injected intraocularly in a mouse model of retinal neovascularization (oxygen-induced retinopathy [OIR]). Cytotoxicity and cell migration assays were used to determine the effect of VEGF-A(165)b. RESULTS. VEGF-A(165)b dose dependently inhibited angiogenesis (IC50, 12.6 pg/eye) and retinal endothelial migration induced by 1 nM VEGF-A(165) across monolayers in culture (IC50, 1 nM). However, it also acts as a survival factor for endothelial cells and retinal epithelial cells through VEGFR2 and can stimulate downstream signaling. Furthermore, VEGF-A(165)b injection, while inhibiting neovascular proliferation in the eye, reduced the ischemic insult in OIR (IC50, 2.6 pg/eye). Unlike bevacizumab, pegaptanib did not interact directly with VEGF-A(165)b. CONCLUSIONS. The survival effects of VEGF-A(165)b signaling can protect the retina from ischemic damage. These results suggest that VEGF-A(165)b may be a useful therapeutic agent in ischemia-induced angiogenesis and a cytoprotective agent for retinal pigment epithelial cells. (Invest Ophthalmol Vis Sci. 2010; 51:4273-4281) DOI:10.1167/iovs.09-4296
引用
收藏
页码:4273 / 4281
页数:9
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