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European Journal of Heart Failure Advance Access originally published online on January 12, 2009
European Journal of Heart Failure 2009 11(3):246-255; doi:10.1093/eurjhf/hfn027
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org

Enhanced myogenic constriction of mesenteric artery in heart failure relates to decreased smooth muscle cell caveolae numbers and altered AT1- and epidermal growth factor-receptor function

Ying Xu1,*, Rob H. Henning1, Maria Sandovici1, Johannes J. van der Want2, Wiek H. van Gilst1 and Hendrik Buikema1

1 Department of Clinical Pharmacology, Groningen University Institute for Drug Exploration (GUIDE), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
2 Department of Cell Biology-Electron Microscopy, Groningen University Institute for Drug Exploration (GUIDE), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

* Corresponding author: Heart Science Centre, National Heart and Lung Institute, Imperial College London, Harefield Hospital, Harefield, Middlesex UB9 6JH, UK. Tel: +44 1895 828726, Fax: +44 1895 828900, Email: y.xu{at}imperial.ac.uk


  Abstract

Aims: We previously showed that enhanced myogenic constriction (MC) of peripheral resistance arteries involves active AT1 receptors in chronic heart failure (CHF). Recent data suggest both transactivation of EGF receptors and caveolae-like microdomains to be implicated in the activity of AT1 receptors. Thus, we assessed their roles in increased MC in mesenteric arteries of CHF rats.

Methods and results: Male Wistar rats underwent myocardial infarction to induce CHF and were sacrificed after 12 weeks. The number of caveolae in smooth muscle cells (SMC) of mesenteric arteries of CHF rats was decreased by 43.6 ± 4.0%, this was accompanied by increased MC, which was fully normalized to the level of sham by antagonists of the AT1-receptor (losartan) or EGF-receptor (AG1478). Acute disruption of caveolae in sham rats affected caveolae numbers and MC to a similar extent as CHF, however MC was only reversed by the antagonist of the EGF-receptor, but not by the AT1-receptor antagonist. Further, in sham rats, MC was increased by a sub-threshold concentration of angiotensin II and reversed by both AT1- as well as EGF-receptor inhibition. In contrast, increased MC by a sub-threshold concentration of EGF was only reversed by EGF receptor inhibition.

Conclusion: These findings provide the first evidence that decreased SMC caveolae numbers are involved in enhanced MC in small mesenteric arteries, by affecting AT1- and EGF-receptor function. This suggests a novel mechanism involved in increased peripheral resistance in CHF.

Key Words: Chronic heart failure • Myogenic constriction • Caveolae • AT1 receptor • EGF receptor

Received December 1, 2007; Revised September 4, 2008; Accepted November 12, 2008


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