Abstract. Experimental hypercholesterolemia (HC) may lead to microvascular neovascularization, but the underlying pathogenic mechanism remains unclear. We tested the hypothesis that HC-induced intra-renal neovascularization is associated with inflammation and increased oxidative stress, and would be prevented by chronic antioxidant intervention. Kidneys were excised from pigs after a 12-wk normal (n ϭ 10) or HC diet (n ϭ 8), or HC diet supplemented daily with antioxidant vitamins C (1 g) and E (100 IU/kg) (HC ϩ vitamins, n ϭ 7). Renal cortical samples were then scanned three dimensionally with micro-computed tomography, and microvessels were counted in situ. Blood and tissue samples were removed for measurements of superoxide dismutase (SOD) activity, protein expression of the NADP(H)-oxidase subunits gp91phox, p47phox, and p67phox, vascular endothelial growth factor (VEGF) levels and mRNA, VEGF receptors (Flt-1 and Flk-1), the proinflammatory transcription factor NFB, and the oxidized LDL receptor LOX-1. Microvascular spatial density was significantly elevated in HC compared with normal kidneys but preserved in HC ϩ vitamins. Expression of gp91phox and p67phox was decreased in HC pigs after antioxidant intervention, and SOD improved. The increased renal expression of VEGF and Flk-1 in HC was blunted in HC ϩ vitamins, as were the significant increases in LOX-1, NFB, and interstitial fibrosis. This study shows that renal cortical neovascularization elicited by diet-induced HC is associated with renal inflammation, fibrosis, and upregulation of VEGF and its receptor Flk-1, likely mediated by increased endogenous oxidative stress. Chronic antioxidant supplementation may preserve the kidney in HC.

Advanced hypertension (HT), associated with left ventricular hypertrophy (LVH), impairs myocardial microvascular function and structure and leads to increased myocardial hypoxia and growth factor activation. However, the effect of HT on microvascular architecture and its relation to microvascular function, prior to the development of LVH (early HT), remain unclear.Methods-Pigs were studied after 12 weeks of renovascular HT (n=7) or control (n=7). Myocardial microvascular function (blood volume and blood flow at baseline and in response to adenosine) was assessed using electron beam computed-tomography (CT). Microvascular architecture was subsequently studied ex-vivo using micro-CT, and microvessels (diameter<500μm) counted in-situ in 3-D images (40μm on-a-side cubic voxels). Myocardial expression of vascular endothelial growth factor, basic fibroblast growth factor, and hypoxia inducible factor-1α were also measured.Results-Left ventricular muscle mass was similar between the groups. The blood volume response to intravenous adenosine was attenuated in HT compared to normal animals (+7.4±17.0 vs. +46.2 ±12.3 % compared to baseline, p=0.48 and p=0.01, respectively). Microvascular spatial density in HT was significantly elevated compared to normal (246±26 vs. 125±20 vessels/cm 2 , p<0.05) and correlated inversely with the blood volume response to adenosine. Growth factors expression was increased in HT compared to control. Conclusion-EarlyHT elicits changes in myocardial microvascular architecture, which are associated with microvascular dysfunction and precede changes in muscle mass. These observations underscore the direct and early effects of HT on the myocardial vasculature.

No abstract

No abstract