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      Intact Endothelium-Dependent Dilation and Conducted Responses in Resistance Vessels of Hypercholesterolemic Mice in vivo

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          Atherosclerosis and hyperlipidemia impair endothelium-dependent nitric oxide (NO)-mediated dilations in conducting arteries. In addition to NO, the endothelium releases an endothelium-derived hyperpolarizing factor (EDHF) in response to acetylcholine (ACh), which is particularly important in microvessels and initiates a dilation that conducts along the vessel through gap junctional communication. The expression of connexins is, however, altered by hypercholesterolemia. Therefore, we studied endothelium-dependent dilations and their conduction in murine hypercholesterolemic models. Dilations were assessed by intravital microscopy in arterioles with a diameter of ∼35 µm in ApoE and LDL receptor (LDLR<sup>–/–</sup>)-deficient mice after superfusion or locally confined application of ACh. ACh induced comparable concentration-dependent dilations in wild-type, LDLR<sup>–/–</sup>, and ApoE<sup>–/–</sup> mice fed a normal or high-cholesterol diet, however EC<sub>50</sub> was slightly higher in ApoE<sup>–/–</sup> mice. Furthermore, the NO donor sodium-nitroprusside dilated arterioles to a similar extent (∼60%). Locally initiated ACh dilations (∼68%) conducted up to a distance of 1,100 µm without significant attenuation even under severe hypercholesterolemic conditions. Since ACh dilation in the arterioles of mice is mainly mediated via EDHF, we conclude that hypercholesterolemia does not alter EDHF release and efficacy. This conclusion is confirmed by an intact conducted response since EDHF is a prerequisite for this response. The intact conduction also suggests that gap-junctional communication is functionally preserved in these models.

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          Most cited references 25

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          The gap junction communication channel.

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            Site specificity of atherosclerosis: site-selective responses to atherosclerotic modulators.

            Atherosclerosis is a complex disease process that affects very specific sites of the vasculature. It is recognized that hemodynamic forces are largely responsible for dictating which vascular sites are either susceptible or resistant to developing atherosclerosis. In addition, a number of systemic and local factors also modulate the pathogenesis of the disease. By studying the development of atherosclerosis in mice, investigators have gained insights into the molecular mechanisms of this disease, although studies have largely focused on a single vascular site. Here, we review those recent studies in which vascular site-specific effects on atherosclerosis were reported when more than 1 site was examined. We assess the hypothesis that regional differences in the hemodynamic profile prime the endothelial phenotype to respond distinctly to such systemic risk factors as hypercholesterolemia, genetics, immune status, gender, and oxidative stress. Because a given treatment may differentially affect the development of atherosclerotic lesions throughout the vasculature, the sites chosen for study are critically important. By accounting for the complex interplay of factors that may operate at these different sites, a more complete understanding of the overriding mechanisms that control the initiation and progression of the atherosclerotic lesion may be realized.
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              Defective smooth muscle regulation in cGMP kinase I-deficient mice.

              Regulation of smooth muscle contractility is essential for many important biological processes such as tissue perfusion, cardiovascular haemostasis and gastrointestinal motility. While an increase in calcium initiates smooth muscle contraction, relaxation can be induced by cGMP or cAMP. cGMP-dependent protein kinase I (cGKI) has been suggested as a major mediator of the relaxant effects of both nucleotides. To study the biological role of cGKI and its postulated cross-activation by cAMP, we inactivated the gene coding for cGKI in mice. Loss of cGKI abolishes nitric oxide (NO)/cGMP-dependent relaxation of smooth muscle, resulting in severe vascular and intestinal dysfunctions. However, cGKI-deficient smooth muscle responded normally to cAMP, indicating that cAMP and cGMP signal via independent pathways, with cGKI being the specific mediator of the NO/cGMP effects in murine smooth muscle.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                December 2005
                20 October 2005
                : 42
                : 6
                : 475-482
                Physiologisches Institut, Universität Lübeck, Lübeck, Germany
                88101 J Vasc Res 2005;42:475–482
                © 2005 S. Karger AG, Basel

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                Page count
                Figures: 5, Tables: 2, References: 35, Pages: 8
                Research Paper


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