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Increased caveolae density and caveolin-1 expression accompany impaired NO-mediated vasorelaxation in diet-induced obesity

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Abstract

Diet-induced obesity induces changes in mechanisms that are essential for the regulation of normal artery function, and in particular the function of the vascular endothelium. Using a rodent model that reflects the characteristics of human dietary obesity, in the rat saphenous artery we have previously demonstrated that endothelium-dependent vasodilation shifts from an entirely nitric oxide (NO)-mediated mechanism to one involving upregulation of myoendothelial gap junctions and intermediate conductance calcium-activated potassium channel activity and expression. This study investigates the changes in NO-mediated mechanisms that accompany this shift. In saphenous arteries from controls fed a normal chow diet, acetylcholine-mediated endothelium-dependent vasodilation was blocked by NO synthase and soluble guanylyl cyclase inhibitors, but in equivalent arteries from obese animals sensitivity to these agents was reduced. The expression of endothelial NO synthase (eNOS) and caveolin-3 in rat saphenous arteries was unaffected by obesity, whilst that of caveolin-1 monomer and large oligomeric complexes of caveolins-1 and -2 were increased in membrane-enriched samples. The density of caveolae was increased at the membrane and cytoplasm of endothelial and smooth muscle cells of saphenous arteries from obese rats. Dissociation of eNOS from caveolin-1, as a prerequisite for activation of the enzyme, may be compromised and thereby impair NO-mediated vasodilation in the saphenous artery from diet-induced obese rats. Such altered signaling mechanisms in obesity-related vascular disease represent significant potential targets for therapeutic intervention.

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Acknowledgments

This study was supported by the National Health and Medical Research Council of Australia (grant ID455243 to S.L.S. and M.J.M.).

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Authors and Affiliations

  1. Department of Pharmacology, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2052, Australia

    T. Hilton Grayson, Preet S. Chadha, Margaret J. Morris & Shaun L. Sandow

  2. Department of Physiology, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2052, Australia

    Paul P. Bertrand, Sevvandi Senadheera, Timothy V. Murphy & Shaun L. Sandow

  3. Ion Channels and Cell Signalling Centre, Basic Medical Sciences Division, St George’s, University of London, Cranmer Terrace, London, SW17 0RE, UK

    Preet S. Chadha

  4. Medical and Molecular Biosciences, University of Technology, Sydney, NSW, 2007, Australia

    Hui Chen

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  1. T. Hilton Grayson
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Grayson, T.H., Chadha, P.S., Bertrand, P.P. et al. Increased caveolae density and caveolin-1 expression accompany impaired NO-mediated vasorelaxation in diet-induced obesity. Histochem Cell Biol 139, 309–321 (2013). https://doi.org/10.1007/s00418-012-1032-2

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