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(Circulation. 2008;118:828-836.)
© 2008 American Heart Association, Inc.

Hypertension

Smoothelin-B Deficiency Results in Reduced Arterial Contractility, Hypertension, and Cardiac Hypertrophy in Mice

Sander S. Rensen, PhD; Petra M. Niessen, PhD; Jan M. van Deursen, PhD; Ben J. Janssen, PhD; Edwin Heijman, MS; Evelien Hermeling, MS; Merlijn Meens, MS; Natascha Lie, MD; Marion J. Gijbels, PhD; Gustav J. Strijkers, PhD; Pieter A. Doevendans, MD, PhD; Marten H. Hofker, PhD; Jo G.R. De Mey, PhD; Guillaume J. van Eys, PhD

From the Departments of Genetics and Cell Biology (S.S.R., P.M.N., N.L., M.J.G., M.H.H., G.J.v.E.), Pharmacology and Toxicology (B.J.J., M.M., J.G.R.D.M.), Biophysics (E. Hermeling, G.J.S.), and Cardiology (P.A.D.), Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands; Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, Minn (J.M.v.D.); and Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands (E. Heijman, G.J.S.).

Correspondence to G. van Eys, PhD, Department of Genetics and Cell Biology, Maastricht University, PO Box 616, 6200 MD Maastricht, the Netherlands. E-mail g.vaneys{at}gen.unimaas.nl

Received October 4, 2007; accepted June 20, 2008.

Background— Smoothelins are actin-binding proteins that are abundantly expressed in healthy visceral (smoothelin-A) and vascular (smoothelin-B) smooth muscle. Their expression is strongly associated with the contractile phenotype of smooth muscle cells. Analysis of mice lacking both smoothelins (Smtn-A/B^–/– mice) previously revealed a critical role for smoothelin-A in intestinal smooth muscle contraction. Here, we report on the generation and cardiovascular phenotype of mice lacking only smoothelin-B (Smtn-B^–/–).

Methods and Results— Myograph studies revealed that the contractile capacity of the saphenous and femoral arteries was strongly reduced in Smtn-B^–/– mice, regardless of the contractile agonist used to trigger contraction. Arteries from Smtn-A/B^–/– compound mutant mice exhibited a similar contractile deficit. Smtn-B^–/– arteries had a normal architecture and expressed normal levels of other smooth muscle cell–specific genes, including smooth muscle myosin heavy chain, -smooth muscle actin, and smooth muscle-calponin. Decreased contractility of Smtn-B^–/– arteries was paradoxically accompanied by increased mean arterial pressure (20 mm Hg) and concomitant cardiac hypertrophy despite normal parasympathetic and sympathetic tone in Smtn-B^–/– mice. Magnetic resonance imaging experiments revealed that cardiac function was not changed, whereas distension of the proximal aorta during the cardiac cycle was increased in Smtn-B^–/– mice. However, isobaric pulse wave velocity and pulse pressure measurements indicated normal aortic distensibility.

Conclusions— Collectively, our results identify smoothelins as key determinants of arterial smooth muscle contractility and cardiovascular performance. Studies on mutations in the Smtn gene or alterations in smoothelin levels in connection to hypertension in humans are warranted.

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CLINICAL PERSPECTIVE

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