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      Conducted Vasoconstriction Is Reduced in a Mouse Model of Sepsis

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          The ability of an arteriole to conduct vasomotor responses along its length contributes to the control of organ perfusion. Sepsis, a systemic inflammatory response to infection, may compromise this control. We aimed to determine whether sepsis, induced by cecal ligation and perforation (CLP), reduces conducted vasoconstriction 24 h post-CLP. We locally stimulated mouse cremaster arterioles with KCl, measured the resulting local and the conducted constriction (500 µm upstream) and, based on these measurements, determined the communication ratio (CR<sub>500</sub>) as an index of the conducted response. Sepsis significantly reduced the CR<sub>500</sub> from 0.75 to 0.20. Based on a mathematical model, this reduction was predicted to have a significant impact on blood flow control. In septic mice, either a 1-hour washout of the cremaster muscle with physiological saline or a treatment of this muscle with the tyrosine kinase inhibitor PP-2 (100 n M) restored the CR<sub>500</sub> to the control level. Treatment of septic arterioles with the nitric oxide synthase inhibitor N<sup>ω</sup>-nitro- L-arginine methyl ester (100 µ M) partially restored the CR<sub>500</sub> from 0.2 to 0.4. In control mice, lipopolysaccharide (LPS; 10 µg/ml) superfused over the cremaster muscle for 1 h reduced the CR<sub>500</sub>; the nitric oxide (NO) donor S-nitroso-N-acetyl-penicillamine (50 µ M) also reduced the CR<sub>500</sub>. Thus, LPS and NO could be two factors mediating reduced conduction of vasoconstriction in sepsis. We conclude that sepsis reduces the KCl-induced conducted vasoconstriction in the mouse cremaster muscle by a tyrosine kinase- and nitric oxide- dependent mechanism.

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          Most cited references 11

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          Connections with Connexins: the Molecular Basis of Direct Intercellular Signaling

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            Altered pattern of vascular connexin expression in atherosclerotic plaques.

            Paracrine cell-to-cell interactions are crucial events during atherogenesis. However, little is known about the role of direct intercellular communication via gap junctions during this process. We have investigated the expression pattern of 3 vascular gap junction proteins (connexins) in mouse and human atherosclerotic plaques. Low density lipoprotein receptor-deficient mice were fed a high-fat diet for 0, 6, 10, or 14 weeks to induce different stages of atherosclerosis. Connexin37 (Cx37) and Cx40 were detected in the endothelium, and Cx43 was detected in the media of nondiseased aortas. In early atheromas, endothelial and medial connexin expression remained unchanged, and "islets" of Cx43 in smooth muscle cells and Cx37 in macrophages were observed in the neointima. In advanced atheromas, Cx37 was detected in medial smooth muscle cells and in macrophages in the lipid core but not in the endothelium covering the plaques. Cx40 could also no longer be detected in the endothelium covering the plaques. Cx43, on the other hand, was detected in the endothelium covering the shoulder of the plaques and also sparsely in neointimal smooth muscle cells. Similar results were obtained for human carotid arteries. In conclusion, vascular connexins are differentially expressed by atheroma-associated cells within lesions. These observations suggest a role for gap junctional intercellular communication during atherogenesis.
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              Endothelium-specific replacement of the connexin43 coding region by a lacZ reporter gene.

              The murine gap junction protein connexin43 (Cx43) is expressed in blood vessels, with vastly different contribution by endothelial and smooth muscle cells. We have used the Cre recombinase under control of TIE2 transcriptional elements to inactivate a floxed Cx43 gene specifically in endothelial cells. Cre-mediated deletion led to replacement of the Cx43 coding region by a lacZ reporter gene. This allowed us to monitor the extent of deletion and to visualize the endothelial expression pattern of Cx43. We found widespread endothelial expression of the Cx43 gene during embryonic development, which became restricted largely to capillaries and small vessels in all adult organs examined. Mice lacking Cx43 in endothelium did not exhibit altered blood pressure, in contrast to mice deficient in Cx40. Our results show that lacZ activation after deletion of the target gene allows us to determine the extent of cell type-specific deletion after phenotypical investigation of the same animal.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                April 2003
                19 June 2003
                : 40
                : 2
                : 149-158
                aLawson Health Research Institute, bChild Health Research Institute and Departments of cMedical Biophysics, dPaediatrics and ePhysiology, University of Western Ontario, London, Ontario, Canada
                70712 J Vasc Res 2003;40:149–158
                © 2003 S. Karger AG, Basel

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                Page count
                Figures: 7, References: 38, Pages: 10
                Research Paper


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