Inhibition of CXCR4 Suppresses Ocular Neovascularization

Abstract

Abstract: : Purpose: Agents that stimulate or inhibit angiogenesis in one vascular bed do not necessarily have the same effect in other vascular beds. The CXC chemokine family has been found to promote angiogenesis in some tissues but effects in the eye are unknown. In this study, we used inhibitors for CXC receptor 4 (CXCR4) to explore the role of CXC chemokines in ocular neovascularization. Methods: Adult C57BL/6 mice had laser–induced rupture of Bruch’s membrane at 3 locations in each eye and were treated with one of three CXCR4 inhibitors, AMD8664, TC14012, or Merck CXCR4 inhibitor (compound 3) by various routes of administration. Two weeks later, mice were perfused with fluorescein–labeled dextran and CNV was measured on choroidal flat mounts by image analysis. Results: Daily periocular injections of 50 mg/kg of TC14012 or compound 3 (30.3% and 63.5 % reductions, respectively), but not AMD8664, caused significant suppression of choroidal neovascularization (CNV) lesion size. In contrast, intravitreous injection of 1 µg or 10 µg/ml of AMD8664 as well as compound 3 significantly suppressed CNV. Compared to vehicle–injected controls, eyes injected with AMD8664 or compound 3 had reductions in CNV area of 50.9 or 61.7%, respectively. In rho/VEGF transgenic mice, periocular injection of TC14012 reduced subretinal neovascularization by 50%. Conclusions: Blockade of CXCR4 suppresses CNV. The action of the inhibitors seems to be local at the site of CNV, because intravitreous injection of each of the 3 inhibitors had a suppressive effect. The lack of efficacy for periocular AMD8664 may be related to pharmacokinetics. The mechanism is likely to involve something other than down–regulation of VEGF, because one of the agents suppressed neovascularization in transgenic mice with constitutive overexpression of VEGF.

Keywords: choroid: neovascularization • laser • drug toxicity/drug effects