Abstract 456: Enhanced Expression of Aortic and Plasma Vascular Endothelial Growth Factor-C in Experimental Atherosclerosis

Abstract

Background: Members of VEGF family such as VEGF-A has been extensively studied given its association with plaque stability through its modulation on angiogenesis. However, contribution of VEGF-A in angiogenesis during atherosclerosis remains controversial as circulating VEGF-A is shown to have a minor impact on atherosclerosis development. Thus another member of VEGF family, VEGF-C, has been implicated in atherosclerosis as VEGF-C displays dual functions being both angiogenic and lymphangiogenic. In contrast to VEGF-A, little information is available on VEGF-C. Moreover, few studies that investigated VEGF-C expression in atherosclerosis were limited so far to advanced plaques since most of the studies have been performed in post-mortem human aortic tissue. Thus, we conducted an in depth analysis of the temporal and spatial distribution of VEGF-C in aortic tissue from apoE -/- mice as the disease progresses from fatty streaks (or early lesions) to more advanced lesions and also to identify the cellular source of VEGF-C in atherosclerotic lesions. Methods and results: Compared to wild-type mice, expression of VEGF-C was increased in the aorta, more specifically in intimal lesions, of apoE -/- . Within early lesions, monocyte-derived cells were the main VEGF-C producers. The spatial analysis of VEGF-C expression as plaque progresses from fatty streaks to more advanced plaque revealed that intimal VEGF-C correlated with plaque progression and preferentially localized in the fibrous cap and shoulder regions of advanced plaques. Moreover, this increase in tissue VEGF-C was accompanied by an increase in plasma VEGF-C during disease progression. Finally, aortic and plasma VEGF-C levels were markedly reduced in atherosclerotic mice treated with the cholesterol-lowering drug ezetimibe in which plaque regressed. We also showed that macrophages and smooth muscle cells express VEGFR-2 and -3 implying that VEGF-C has other cellular targets and potentially could have effect on these cells. The potential function(s) of VEGF-C in atherosclerosis will be discussed. Conclusions: This study provides the evidence for the close association between VEGF-C and progression of atherosclerosis.