Smoothelin-a is essential for functional intestinal smooth muscle contractility in mice

P.M.G. Niessen, S.S.M. Rensen, J. Deursen, J. de Man, A. de Laet, J.M. Vanderwinden, T. Wedel, D. Baker, P.A.F.M. Doevendans, M.H. Hofker, M.J.J. Gijbels, G.J.J.M. van Eys

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Abstract

BACKGROUND & AIMS: In patients with chronic intestinal pseudo-obstruction, intestinal motility is disturbed by either nervous or myogenic aberrations. The cause of the myogenic form is unknown, but it is likely to originate in the contractile apparatus of the smooth muscle cells. Smoothelins are actin-binding proteins that are expressed abundantly in visceral (smoothelin-A) and vascular (smoothelin-B) smooth muscle. Experimental data indicate a role for smoothelins in smooth muscle contraction. A smoothelin-deficient mouse model may help to establish the role of smoothelin-A in intestinal contraction and provide a model for myogenic chronic intestinal pseudo-obstruction. METHODS: We used gene targeting to investigate the function of smoothelin-A in intestinal tissues. By deletion of exons 18, 19, and 20 from the smoothelin gene, the expression of both smoothelin isoforms was disrupted. The effects of the deficiency were evaluated by pathologic and physiologic analyses. RESULTS: In smoothelin-A/B knockout mice, the intestine was fragile and less flexible compared with wild-type littermates. The circular and longitudinal muscle layers of the intestine were hypertrophic. Deficiency of smoothelin-A led to irregular slow wave patterns and impaired contraction of intestinal smooth muscle, leading to hampered transport in vivo. This caused obstructions that provoked intestinal diverticulosis and occasionally intestinal rupture. CONCLUSIONS: Smoothelin-A is essential for functional contractility of intestinal smooth muscle. Hampered intestinal transit in smoothelin-A/B knockout mice causes obstruction, starvation, and, ultimately, premature death. The pathology of mice lacking smoothelin-A is reminiscent of that seen in patients with chronic intestinal pseudo-obstruction
Original languageEnglish
Pages (from-to)1592-1601
JournalGastroenterology
Volume129
Issue number5
DOIs
Publication statusPublished - 1 Jan 2005

Cite this

Niessen, P. M. G., Rensen, S. S. M., Deursen, J., de Man, J., de Laet, A., Vanderwinden, J. M., Wedel, T., Baker, D., Doevendans, P. A. F. M., Hofker, M. H., Gijbels, M. J. J., & van Eys, G. J. J. M. (2005). Smoothelin-a is essential for functional intestinal smooth muscle contractility in mice. Gastroenterology, 129(5), 1592-1601. https://doi.org/10.1053/j.gastro.2005.08.018