Recombinant human VEGF165b inhibits experimental choroidal neovascularization.
| Autor: | Hua J; Microvascular Research Laboratories, Department of Physiology and Pharmacology, Bristol Heart Institute, School of Veterinary Sciences, University of Bristol, Bristol, UK., Spee C, Kase S, Rennel ES, Magnussen AL, Qiu Y, Varey A, Dhayade S, Churchill AJ, Harper SJ, Bates DO, Hinton DR |
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| Jazyk: | angličtina |
| Zdroj: | Investigative ophthalmology & visual science [Invest Ophthalmol Vis Sci] 2010 Aug; Vol. 51 (8), pp. 4282-8. Date of Electronic Publication: 2010 Mar 17. |
| DOI: | 10.1167/iovs.09-4360 |
| Abstrakt: | Purpose: 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. |
| Databáze: | MEDLINE |
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