Choroidal neovascularization in age-related macular degeneration depends on vascular endothelial growth factor, but vascular endothelial growth factor should not be the promising treatment target

Abstract

Choroidal neovascularization (CNV) in age-related macular degeneration (AMD) may results in severe vision loss. Upregulation of vascular endothelial growth factor (VEGF) in hypoxic retinal pigment epithelium (RPE), mediated by hypoxia-inducible factor 1 (HIF-1) is responsible for CNV. Hypoxia triggers ATP-deletion in RPE cells, which activates HIF-1 via the Rho GTPase. HIF-1 also activates the expression of other growth factors, which upregulate the expression of corresponding receptors on the membrane of choroidal endothelial cells (CECs). Activation of these growth factor receptors itself activates Rho GTPases, and hence HIF-1 and VEGF transcription. There is therefore an autocrine pathway of VEGF activation in these cells, as well as paracrine stimulation of the VEGF pathway from external VEGF. At present, the pivot of treating CNV is blocking VEGF, which however will only block the paracrine pathway. We suggest that the promising treatment target for CNV in AMD should be transferred to upstream of VEGF, such as HIF-1 or Rho family GTPases family.