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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1934.)
© 2007 American Heart Association, Inc.

Vascular Biology

RhoA Activation Contributes to Sex Differences in Vascular Contractions

Daniel W. Nuno; Victoria P. Korovkina; Sarah K. England; Kathryn G. Lamping

From the Veterans Affairs Medical Center (D.W.N., K.G.L.) and the Departments of Internal Medicine (D.W.N., K.G.L.), Pharmacology (K.G.L.), and Molecular Physiology and Biophysics (V.P.K., S.K.E.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City.

Correspondence to Kathryn Lamping, PhD, VA Medical Center, 10W16, 601 Highway 6 West, Iowa City, IA 52246. E-mail Kathryn-lamping{at}uiowa.edu

Objective— Studies have suggested that sex differences in endothelial function in part account for the lower incidence of cardiovascular disease in premenopausal women compared with men. Less is known about the role of smooth muscle. We hypothesized that signaling mechanisms that regulate calcium sensitivity in vascular muscle also play a role in determining sex differences in contractile function.

Methods and Results— In aorta, concentration-dependent contractions to serotonin were greater in male versus female mice whereas contractions to KCl and U46619 were similar. Nitric oxide or other endothelial-derived factors did not account for the difference in responses to serotonin because inhibition of nitric oxide synthase (NOS) with N^G-nitro-L-arginine, genetic deficiency of endothelial NOS, and removal of endothelium increased contractions but did not abolish the enhanced contractions in aorta from males. Contractions in aorta from both males and females were abolished by a serotonergic 5HT_2A receptor antagonist (ketanserin), however there was no sex difference in 5HT_2A receptor expression. Activation of RhoA and Rho-kinase by serotonin was greater in aorta from males compared with females, but this was not related to greater expression of RhoA or Rho-kinase isoforms (ROCK1 and ROCK2). The sex difference in aortic contractions to serotonin was abolished by an inhibitor of Rho-kinase, Y27632.

Conclusion— We conclude that increased contractions to serotonin in aorta from male mice are attributable to differences in RhoA/Rho-kinase activation in smooth muscle independent of differences in the expression of RhoA or Rho-kinase.

Aorta from male mice contracted to serotonin more than aorta from females because of an increased activation of RhoA and Rho-kinase and not differences in nitric oxide. This increased activity was not related to differences in the expression of the serotonin receptor 5HT_2A or components of the Rho/Rho-kinase pathway.

Key Words: gender • Rho GTPase • serotonin • Rho-kinase

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