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Distinct endothelial pathways underlie sexual dimorphism in vascular auto-regulation

Item Type:Article
Title:Distinct endothelial pathways underlie sexual dimorphism in vascular auto-regulation
Creators Name:Chan, M.V. and Bubb, K.J. and Noyce, A. and Villar, I.C. and Duchene, J. and Hobbs, A.J. and Scotland, R.S. and Ahluwalia, A.
Abstract:Background and purpose: Pre-menopausal females have a lower incidence of cardiovascular disease compared to age-matched males. Differences in the mechanisms/pathways regulating vasoactivity have been implicated. Small arteries constrict in response to rises in intraluminal pressure; a response termed myogenic tone that is a major determinant of vascular resistance. Endothelium-derived dilators, particularly nitric oxide (NO), tonically moderate myogenic tone and, since the endothelium is an important target for female sex hormones, we investigated whether NO-mediated moderation of myogenic tone differs between the sexes. Experimental approach: Pressure-diameter or relaxation concentration-response curves to NO donor Spermine-NO or soluble guanylate cyclase (sGC) stimulation (BAY41-2272) were constructed before and following drug intervention in murine mesenteric resistance arteries. Hypotensive responses to activators of the NO-sGC pathway were determined. Quantitative PCR and western blotting were used for expression analysis. Key results: NO synthase inhibition enhanced myogenic tone of arteries of both sexes whilst block of endothelium-derived hyperpolarising factor (EDHF) enhanced responses in arteries of females only. Spermine-NO caused concentration-dependent relaxation of mesenteric arteries isolated from either sex. However, whilst inhibition of sGC activity attenuated responses of arteries from male mice only, endothelium-denudation attenuated responses of arteries from female mice only. BAY41-2272 and Spermine-NO-induced vasodilatation and hypotension were enhanced in males vs females. Conclusions and implications: These data demonstrate that NO moderates myogenic tone in arteries of male mice via an sGC-dependent pathway whilst EDHF is the predominant endothelial regulator in arteries of females. We have identified a potentially important sexual dimorphism in NO-mediated reactivity and further implicate EDHF as the predominant endothelial vasodilator in female resistance arteries.
Keywords:Sex, Nitric Oxide, Vascular, Animals, Mice
Source:British Journal of Pharmacology
Page Range:805-817
Date:October 2012
Official Publication:https://doi.org/10.1111/j.1476-5381.2012.02012.x
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