Abstract
Blinding diseases including retinopathy of prematurity and proliferative diabetic retinopathy are the consequence of pathological angiogenesis in the retina. A better understanding of the mechanisms involved in this abnormal proliferation of neovessels appears to be essential to develop drugs against new molecular targets. Recently, we have evidenced that Fzd7 receptor, a member of the Wnt/Fzd family, is required for retinal postnatal angiogenesis. This study aimed to investigate the role of Fzd7 during aberrant angiogenesis in a model of ischemic retinopathy. We used mice model of OIR to explore the involvement of Fzd7 during initial vaso-obliteration (VO) and subsequent neovascularization (NV) phases. By transgenic approaches, we observed that deletion of fzd7 in the endothelium ( fzd7 ECKO ) resulted in increased retinal tissue sensitivity to hypoxia during the VO phase of OIR. Moreover, fzd7 deletion in EC reduced the ectopic growth of pathologic neovessels into the vitreous during the NV phase (P17) demonstrating that Fzd7 was involved in pathological NV formation in mice retina during OIR. To determine how Fzd7 may regulate ischemic retinopathy, we explored canonical β-catenin and Notch signaling during OIR and showed that transcript expressions of lef1, axin2 and partners of Notch signaling were strongly decreased in fzd7 ECKO retina mice as compared to control. To evaluate therapeutic potential of Fzd7 blocking, we experimented 2 strategies: a monoclonal antibody (MabFzd7) and a soluble Fzd7 receptor (CRD domain). In vitro both MabFzd7 and Fzd7CRD decreased the activity of β-catenin reporter gene induced by Wnt3A in EC. In vivo intravitreal microinjection of MabFzd7 or intraperitoneal injection of Fzd7CRD in mice at P12 decreased neovessels in the treated eye compared to the control eye at P17. By controlling development of abnormal vascularization, Fzd7 could be a new target to develop promising anti-angiogenic drugs in the treatment of ischemic retinopathies. The author hereby declares no conflict of interest
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