Simvastatin Preserves the Structure of Coronary Adventitial Vasa Vasorum in Experimental Hypercholesterolemia Independent of Lipid Lowering

Abstract

Background-Previous studies have demonstrated that experimental hypercholesterolemia leads to neovascularization in the coronary artery vasa vasorum (VV). Recent evidence suggests that HMG-CoA reductase inhibitors (statins) have beneficial effects independent of lipid lowering. We aimed to determine the effect of simvastatin on coronary VV neovascularization, in the absence of cholesterol lowering. Methods and Results-Pigs were randomized to 3 groups fed a normal (N), high cholesterol (HC), or HCϩsimvastatin (HCϩS) diet for 12 weeks. The proximal left anterior descending artery was isolated, scanned with micro-CT, and reconstructed. Quantification of the VV density in serial cross-sections along the vessel was then performed. LDL cholesterol was similarly increased in HC and HCϩS compared with N. There was an increase in both VV density (4.

Vitamins C and E downregulate vascular VEGF and VEGFR-2 expression in apolipoprotein-E-deficient mice

“…VEGF and VEGFR-2 expression were measured in apoE−/− mice, an accepted model of atherosclerosis showing high cholesterol concentration, increased lipid peroxidation [11] and low nitric oxide bioavailability [12]. We found higher levels of aorta and plasma VEGF in apoE−/− than in WT, in agreement with previous observations in the coronary arteries of hypercholesterolemic pigs [14], as well as in the plasma of hypercholesterolemic patients [13]. Moreover, increased vascular VEGF was accompanied by a marked upregulation in VEGFR-2 expression, a novel finding not described previously in hypercholesterolemia.…”

“…Although the mechanism by which hypercholesterolemia may induce VEGF upregulation in the vessel wall remains unclear, possible pathophysiological stimuli include hypoxia [14], oxidative stress [3] and low NO bioavailability [4]. Moreover, VEGF upregulation has been proposed to be a non-specific stress-induced vascular response in the adult organism [25], or to constitute a vascular homeostatic mechanism for compensating endothelial dysfunction [1].…”

“…Increased VEGF levels have been reported in plasma from hypercholesterolemic individuals [13] and in coronary arteries from hypercholesterolemic pigs [14]. Moreover, it has been shown that oxidized LDL, a key molecule in the atherosclerotic process, can upregulate VEGF expression in macrophages and endothelial cells, at least partially through the activation of PPAR␥ [15].…”

Three‐dimensional arrangement of the vasa vasorum in explanted segments of the aged human great saphenous vein: Scanning electron microscopy and three‐dimensional morphometry of vascular corrosion casts

“…A comparison with the findings gained by -CT (Kwon et al, 1998;Wilson et al, 2002;Gössl et al, 2003) clearly shows that -CT lacks all capillaries and pre-and postcapillary vessels smaller than ϳ 40 m. Here, SEM of corrosion casts is superior to the previous technique, as it enables the detailed study of each microcirculatory unit of the vasa vasorum and thus allows the origin and merging of individual vessels to be clearly defined. As vascular casts made from Mercox-CL-2B tend to be very brittle, superficial vessels hiding vessels underneath can be removed with the help of a fine tipped insect pin and thus visualization of successive layers of vessels becomes possible.…”

Endothelial α ν β 3 Integrin–Targeted Fumagillin Nanoparticles Inhibit Angiogenesis in Atherosclerosis

“…The importance of angiogenesis in the progression of atherosclerotic plaque combined with the antiangiogenic impact of 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors, 12 suggests that suppression of vasa vasorum expansion could stabilize or reverse disease progression. Antiangiogenic agents have been shown to decrease both neovascular proliferation and plaque development in animal models of atherosclerosis when administered chronically at high dosages.…”