γ-Secretase Regulates VEGFR-1 Signalling in Vascular Endothelium and RPE

Neovascular diseases of the eye include retinopathy of prematurity (ROP), proliferative diabetic retinopathy (PDR), and the exudative or “wet” form of age-relatedmacular degeneration (AMD). Together these diseases affect all age groups and are the leading causes of vision impairment in developed nations (Lee et al., 1998). The collective evidence suggests that the vascular endothelial growth factor (VEGF) family is critical for ocular angiogensis (Cai and Boulton, 2002; Grant et al., 2004). First, increasing VEGF in animal models promotes ocular neovascularization and this can be reversed by neutralizing VEGF or its receptors(vanWijngaarden et al., 2005; Witmer et al., 2003). Second, VEGF is hypoxia-inducible and thus dramatically upregulated by the hypoxic environment in ROP and PDR (Grant et al., 2004; Witmer et al., 2003). Third, treatment of AMD patients with CNV with VEGF inhibitors such as Macugen or Lucentis significantly reduces choroidal neovascularization (vanWijngaarden et al., 2005).