Augustin Table 3 Summary of the in vitro and in vivo models of neovascularization used to evaluate the antiangiogenic properties of anecortave acetate Models References Human vascular endothelial cells Chicken embryo CAM Rabbit corneal NV Retinal NV in newborn mice Light-induced retinal NV in RCS rats Murine intraocular tumor Kitten retinopathy of prematurity Rat pup retinopathy of prematurity Mouse laser-induced choroidal NV Rabbit choroidal NV Clark et al 2000; DeFaller and Clark 2000; Clark and Yorio 2003 McNatt et al 1999; Clark et al 2000; DeFaller and Clark 2000; Clark and Yorio 2003 BenEzra et al 1997; McNatt et al 1999; Clark et al 2000; DeFaller and Clark 2000; Clark and Yorio 2003 Clark 1997; Clark et al 2000; DeFaller and Clark 2000; Clark and Yorio 2003 Clark 1997; Clark et al 2000; DeFaller and Clark 2000; Clark and Yorio 2003 Clark et al 1999; Clark et al 2000; DeFaller and Clark 2000; Clark and Yorio 2003 Clark et al 2000; DeFaller and Clark 2000; Clark and Yorio 2003 Clark et al 2000; DeFaller and Clark 2000; Penn 2001; Clark and Penn 2003; Clark and Yorio 2003 Clark 1997; Clark et al 2000; DeFaller and Clark 2000; Clark and Penn 2003; Clark and Yorio 2003 Clark et al 2000; DeFaller and Clark 2000; Clark and Yorio 2003 Abbreviations: CAM, cell-adhesion molecule; NV, neovascularization; RCS, Royal College of Surgeons. acetate’s mechanism of action is in part through inhibiting the expression of urokinase plasminogen activator (uPA) and matrix metalloproteinases (MMPs), extracellular proteases necessary for the breakdown of the basement membrane and extracellular matrix necessary for subsequent migration of VECs into tissue stroma during blood vessel growth (DeFaller and Clark 2000). Additionally, anecortave acetate has been demonstrated to stimulate the production of plasminogen activator inhibitor-1 (PAI-1), a specific inhibitor of uPA activity (Penn et al 2001) (Figure 5). In a rat model of retinopathy of prematurity (ROP) retinal levels of PAI-1 and mRNA increased 6- to 9-fold in 24 to 72 hours following intravitreal injection of anecortave acetate (BenEzra et al 1997). Administration of anecortave acetate inhibits the activities of uPA and MMPs. As a result, proteolysis necessary for cellular migration cannot occur and angiogenesis is thus inhibited. Primary angiostatic effects of anecortave acetate on trophic factor release have been demonstrated as well. In one study using the rat ROP model, anecortave acetate reduced the expression of the proangiogenic insulin-like growth factor (IGF-1) and IGF- 1 receptor by 36.9% and 50.5%, respectively (Liu et al 2005). In a similar series of experiments using the same rat ROP model, injection of anecortave acetate also reduced VEGF protein at one and two days post-oxygen exposure. This model also demonstrated that anecortave acetate inhibited the transcription of VEGF mRNA, which is upregulated during angiogenesis (Yang et al 2005). Future studies are on-going to quantify specific VEGF mRNA splice-variants (Figure 1). Figure 2 The unique design of the blunt tinted posterior juxtascleral depot cannula ensures that anecortave acetate is delivered directly behind the macula while leaving the globe intact. 240 Clinical Interventions in Aging 2006:1(3)