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Novel effects of adenosine receptors on pericellular hyaluronan matrix: implications for human smooth muscle cell phenotype and interactions with monocytes during atherosclerosis

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Abstract

Hyaluronan (HA) is responsive to pro-atherosclerotic growth factors and cytokines and is thought to contribute to neointimal hyperplasia and atherosclerosis. However, the specific function of the pericellular HA matrix is likely depend on the respective stimuli. Adenosine plays an important role in the phenotypic regulation of vascular smooth muscle cells (VSMC) and is thought to inhibit inflammatory responses during atherosclerosis. The aim of this study was to examine the regulation and function of HA matrix in response to adenosine in human coronary artery SMC (HCASMC). The adenosine receptor agonist NECA (10 μM) caused a strong induction of HA synthase (HAS)1 at 6 h and a weaker induction again after 24 h. Use of selective adenosine receptor antagonists revealed that adenosine A2B receptors (A2BR) mediate the early HAS1 induction, whereas late HAS1 induction was mediated via A2AR and A3R. The strong response after 6 h was mediated in part via phosphoinositide-3 kinase- and mitogen-activated protein kinase pathways and was inhibited by Epac. Functionally, NECA increased cell migration, which was abolished by shRNA-mediated knock down of HAS1. In addition to HA secretion, NECA also stimulated the formation of pronounced pericellular HA matrix in HCASMC and increased the adhesion of monocytes. The adenosine-induced monocyte adhesion was sensitive to hyaluronidase. In conclusion, the current data suggest that adenosine via adenosine A2BR and A2AR/A3R induces HAS1. In turn a HA-rich matrix is formed by HCASMC which likely supports the migratory HCASMC phenotype and traps monocytes/macrophages in the interstitial matrix.

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Acknowledgment

Funded by the Deutsche Forschungsgemeinschaft (DFG-FI682/3-1).

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  1. Institut für Pharmakologie u. Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, 40225, Düsseldorf, Germany

    M. Grandoch, J. Hoffmann, K. Röck & J. W. Fischer

  2. Institut für Transplantationsdiagnostik und Zelltherapeutika, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, 40225, Düsseldorf, Germany

    F. Wenzel

  3. Klinik für Gefäß- und Endovaskularchirurgie, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, 40225, Düsseldorf, Germany

    A. Oberhuber & H. Schelzig

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Grandoch, M., Hoffmann, J., Röck, K. et al. Novel effects of adenosine receptors on pericellular hyaluronan matrix: implications for human smooth muscle cell phenotype and interactions with monocytes during atherosclerosis. Basic Res Cardiol 108, 340 (2013). https://doi.org/10.1007/s00395-013-0340-6

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