Abstract
Sphingolipids are not only integral membrane components but also vasoactive signaling molecules. We tested the hypothesis that vascular responses to sphingosine‐1‐phosphate (S1P) are augmented in diabetics through abnormal rho kinase and caveolar regulation. We measured responses of isolated pressurized resistance arteries from gracilis muscle of wild type (WT, diameter 101±23μm), caveolin‐1 deficient which lack caveolae (Cav−/−, diameter 130±30μm) and a model of type 2 diabetes in mice [leptin receptor deficient (db/db), diameter 123±11μm] to S1P (1nM‐1μM) and KCl (25–100 mM) in the absence and presence of a rho kinase inhibitor, H1152 (1 μM). S1P produced concentration‐dependent vasoconstriction that was increased 60–70% (P<0.05) in arteries from Cav−/− and db/db mice. H1152 had minimal effect on constriction of arteries from WT mice but inhibited responses in arteries from Cav−/− and db/db mice to the levels of WT. Vasoconstriction to KCl was similar in all groups. We conclude that in type 2 diabetics, responses of resistance arteries in skeletal muscle to S1P are augmented. The increased constriction may be due, in part, to abnormal caveolar localization and/or rho kinase activation. Support: Dept of Veterans Affairs
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