Cyclic AMP Response Element Binding Protein Mediates Pathological Retinal Neovascularization via Modulating DLL4-NOTCH1 Signaling

• In this study we found that VEGFC via CREB activates DLL4-NOTCH1 signaling in the regulation of retinal neovascularization.
• In addition, our findings reveal that p38MAPK acts upstream to CREB in the activation of DLL4-NOTCH1 in the modulation of retinal neovascularization.Despite anti-VEGFA therapies, proliferative retinopathy continues to be a cause of vitreous hemorrhage, retinal detachment, and/or neovascular glaucoma affecting vision. In the present study VEGFC was identified as an enhancer of retinal neovascularization and this effect is dependent on activation of p38β-CREB-DLL4-NOTCH1 signaling. These studies open up a new line of understanding about the pathophysiology of retinal neovascularization. Drug development targeting a combinatorial inhibition of VEGFA and VEGFC could be more beneficial in the treatment of retinal neovascularization as well as other ischemic ocular lesions.

Retinal neovascularization is the most common cause of moderate to severe vision loss in all age groups. Despite the use of anti-VEGFA therapies, this complication continues to cause blindness, suggesting a role for additional molecules in retinal neovascularization. Besides VEGFA and VEGFB, hypoxia induced VEGFC expression robustly. Based on this finding, we tested the role of VEGFC in pathological retinal angiogenesis. VEGFC induced proliferation, migration, sprouting and tube formation of human retinal microvascular endothelial cells (HRMVECs) and these responses require CREB-mediated DLL4 expression and NOTCH1 activation. Furthermore, down regulation of VEGFC levels substantially reduced tip cell formation and retinal neovascularization in vivo. In addition, we observed that CREB via modulating the DLL4-NOTCH1 signaling mediates VEGFC-induced tip cell formation and retinal neovascularization. In regard to upstream mechanism, we found that down regulation of p38β levels inhibited hypoxia-induced CREB-DLL4-NOTCH1 activation, tip cell formation, sprouting and retinal neovascularization. Based on these findings, it may be suggested that VEGFC besides its role in the regulation of lymphangiogenesis also plays a role in pathological retinal angiogenesis and this effect depends on p38β and CREB-mediated activation of DLL4-NOTCH1 signaling.