Vascular endothelial growth factor upregulates expression of annexin A2 in vitro and in a mouse model of ischemic retinopathy

PURPOSE: Annexin A2 has been shown to play a role in many neovascularization diseases. We investigated the effect of vascular endothelial growth factor (VEGF) on annexin A2 expression and related intracellular signaling mechanisms in a mouse model of ischemia-induced retinal neovascularization. METHODS: Annexin A2 expression and the effect of vascular endothelial growth factor (VEGF) on annexin A2 ex pression in retinal neovascularization were assayed by real-time PCR, western blot analysis. The effect of Annexin A2 on retinal neovascularization were assayed by siRNA interference and overexpression of Annexin A2, fluorescence imaging, and immunofluorescence histochemistry in a mouse model of ischemia-induced retinal neovascularization. RESULTS: Expression of annexin A2 mRNA and protein were increased in the mouse model of ischemia-induced retinal neovascularization and in RF/6A cells treated with VEGF. In RF/6A cells, increased expression of annexin A2 was inhibited by the VEGF receptor 2 (VEGFR2) inhibitor SU10944, and by anti-VEGFR2 neutralizing antibody, and was increased by VEGF. Mice with ischemic retinopathy showed increased expression of annexin A2 in vascular endothelial cells, and enhanced retinal neovascularization after intraocular injection of an adenoviral vector containing an annexin A2 expression cassette. Conversely, annexin A2 knockdown suppressed retinal neovascularization in these mice. CONCLUSIONS: These findings suggest that annexin A2 might induce retinal neovascularization through a VEGF-VEGFR2 pathway in ischemia-induced retina neovascularization. Therefore, annexin A2 is an angiogenesis activator and may be a potential target for the development of effective therapeutic strategies for the treatment of retinal neovascularization.