Vascular hypercontractility and endothelial dysfunction before development of atherosclerosis in moderate...

Atherosclerosis is a chronic disease that affects peripheral arteries and the aorta. Several inflammatory processes are required until the production of an atheroma. Before the atheroma appears, endothelial dysfunction is a key event. We hypothesized that endothelial dysfunction occurs in a mouse model of mild dyslipidemia, the mouse deficient in apolipoprotein E (apoE(+/-)). Using aortic rings preparation, we found that apoE(+/-) mice showed increased developed tension in response to KCl 60 mM when using a range a pre-loads from 0.5 to 2.0 grams (p = 0.038). Next, we tested the vasorelaxant capacity of apoE(+/-) aortas (pre-contracted with phenylephrine) in response to acetylcholine, an endothelium-dependent vasodilator. ApoE(+/-) aortas showed diminished vasorelaxation in a range of Ach concentrations (p = 0.0032). Next we assessed the levels of plasma NO metabolites, nitrite plus nitrate. These were significantly reduced, along with a significant decrease of the endothelial nitric oxide synthase in ApoE(+/-) mice. When we analyzed the morphology of the aortas in apoE(+/-) mice, these showed no signs of atheroma. In addition, we analyzed the levels of inflammatory cytokines, TNF-alpha, MCP-1 and interleukin 6 (Il-6). While TNF-alpha was similar in both groups, (18.3 ± 2 pg/mL in wild type vs. 17.5 ± 2 pg/mL in apoE(+/-)), MCP-1 was increased in ApoE deficient mice (71.5 ± 0.8 pg/mL in wild type vs. 85.1 ± 7.4 pg/mL in ApoE(+/-) mice, p = 0.006), along with IL-6 (24.7 ± 1.7 pg/ml in wild type vs. 47.1 ± 12.5 in ApoE mice, p = 0.0055). These results suggest that mild dyslipidemia produces a pro-inflammatory state, associated with diminished NOS and NO production, which produces endothelial dysfunction.