VEGF164 Governs Leukocyte Dynamics and Pathological Neovascularization

Abstract

Abstract: : Purpose: Both physiological vascular development and pathological angiogenesis in the retina have been shown to be controlled by vascular endothelial growth factor (VEGF). Previous studies have demonstrated that ischemia–induced retinal neovascularization is caused in part by local inflammatory responses. This study aims to characterize the roles of the different VEGF isoforms in inflammation and pathological neovascularization by examining the pro–inflammatory and angiogenic nature of the VEGF₁₆₄ isoform through the use of VEGF₁₆₄–deficient (VEGF^120/188) mice. Methods: Retinopathy of prematurity (ROP) and laser induced–choroidal neovascularization (CNV) models were used to investigate the role of VEGF₁₆₄ isoform in pathological neovascularization. In addition, to characterize the role of VEGF₁₆₄ in inflammation outside the eye, we evaluated delayed–type hypersensitivity (DTH) reactions induced by oxazolone in the ear skin of wild–type and VEGF^120/188 mice. Results: VEGF^120/188 mice exhibited normal development of the retinal vasculature, as compared with age–matched wild–type mice, suggesting that the VEGF₁₆₄ isoform is not required for normal vascular development in the retina. However, pathological neovascularization was suppressed by over 90% in the VEGF^120/188 mice when compared with wild–type littermates in the ROP model. Furthermore, leukostasis and up–regulation of intracellular adhesion molecule–1 (ICAM–1) by the vessels were significantly reduced in the retinas of VEGF₁₆₄–deficient mice with ROP, when compared to wild–type littermates. In the CNV model, choroidal neovascularization in the VEGF^120/188 mice was reduced by 44%, as compared with that of wild–type mice. In the DTH model, the lack of the VEGF₁₆₄ isoform resulted in a significant decrease in the inflammatory response which included leukocyte accumulation and tissue edema in ear skin, providing evidence that the pro–inflammatory nature of VEGF₁₆₄ isoform is not unique to ocular tissues. Conclusions: Our data demonstrate that the combination of the VEGF₁₂₀ and VEGF₁₈₈ isoforms are sufficient to drive normal physiological retinal vessel growth, and VEGF₁₆₄ is a pathological VEGF isoform that promotes pathological neovasculariztion as well as inflammation both in the eye and in the skin.

Keywords: neovascularization • inflammation • choroid: neovascularization