Drusen Complement Components C3a and C5a Promote Choroidal Neovascularization

Abstract

Abstract: : Purpose: To determine the role of complement components C3 and C5, which are present in drusen in patients with age–related macular degeneration (AMD) and in our recently described mouse model of AMD, in the development of choroidal neovascularization (CNV). Methods: The effect of C3a and C5a on production of vascular endothelial growth factor (VEGF) was assessed in vitro in human retinal pigmented epithelial (RPE) cells and in vivo by intravitreous injection in C57BL/6J mice. The development of CNV, leukocyte recruitment, VEGF expression, and complement deposition following laser injury was assessed in wild–type and in C3aR–/– and C5aR–/– mice. Results: C3a and C5a induce VEGF expression in vitro in RPE and in vivo in the RPE/choroid. Deposition of C3 and C5 is observed within 6 hours of laser injury in wild–type mice. Following laser injury, there was a reduction in VEGF levels of 60–63%, macrophage recruitment of 42–49%, neutrophil recruitment of 58–67%, and CNV volume of 40–42%, in C3aR–/– and C5aR–/– mice compared to wild–type mice (all Ps < 0.05). Conclusions: Collectively these findings establish a mechanistic basis for the clinical observation that drusen predispose to CNV, both revealing a novel role for immunological phenomena in angiogenesis and providing new therapeutic targets for AMD.

Keywords: age-related macular degeneration • neovascularization