RhoA activation contributes to sex differences in vascular contractions.
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.


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 5HT2A receptor antagonist (ketanserin), however there was no sex difference in 5HT2A 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.


CONCLUSIONS
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.
Nuno
Daniel W
DW
VA Medical Center, 10W16, 601 Highway 6 West, Iowa City, IA 52246, USA.
Korovkina
Victoria P
VP
England
Sarah K
SK
Lamping
Kathryn G
KG
D000818:Animals; D001011:Aorta / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D012701:Serotonin / Q000502:physiology*; D012737:Sex Factors; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000502:physiology*
D047908:Intracellular Signaling Peptides and Proteins; D012701:Serotonin; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D017346:Protein Serine-Threonine Kinases; C515854:Rock1 protein, mouse; C515855:Rock2 protein, mouse; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein