Dataset Information

Distinct endothelial pathways underlie sexual dimorphism in vascular auto-regulation.

ABSTRACT:

Background and purpose

Pre-menopausal females have a lower incidence of cardiovascular disease compared with age-matched males, implying differences in the mechanisms and pathways regulating vasoactivity. In small arteries, myogenic tone (constriction in response to raised intraluminal pressure) is a major determinant of vascular resistance. Endothelium-derived dilators, particularly NO, tonically moderate myogenic tone and, because the endothelium is an important target for female sex hormones, we investigated whether NO-mediated moderation of myogenic tone differed between the sexes.

Experimental approach

Pressure-diameter or relaxation concentration-response curves to the 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 while block of endothelium-derived hyperpolarizing factor (EDHF) enhanced responses in arteries of females only. Spermine-NO concentration-dependently relaxed mesenteric arteries isolated from either sex. However, while inhibition of sGC activity attenuated responses of arteries from male mice only, endothelial denudation attenuated responses of arteries from females only. BAY41-2272 and spermine-NO-induced vasodilatation and hypotension were greater in males than in females.

Conclusions and implications

NO moderated myogenic tone in arteries of male mice by a sGC-dependent pathway while EDHF was the predominant endothelial regulator in arteries of females. This is a potentially important sexual dimorphism in NO-mediated reactivity and further implicates EDHF as the predominant endothelial vasodilator in female resistance arteries.

SUBMITTER: Chan MV

PROVIDER: S-EPMC3575780 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Publications

Distinct endothelial pathways underlie sexual dimorphism in vascular auto-regulation.

Chan Melissa V MV Bubb Kristen J KJ Noyce Alastair A Villar Inmaculada C IC Duchene Johan J Hobbs Adrian J AJ Scotland Ramona S RS Ahluwalia Amrita A

British journal of pharmacology 20121001 4

<h4>Background and purpose</h4>Pre-menopausal females have a lower incidence of cardiovascular disease compared with age-matched males, implying differences in the mechanisms and pathways regulating vasoactivity. In small arteries, myogenic tone (constriction in response to raised intraluminal pressure) is a major determinant of vascular resistance. Endothelium-derived dilators, particularly NO, tonically moderate myogenic tone and, because the endothelium is an important target for female sex h ...[more]

PMID: 22540539

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Project description:Introduction: At the molecular level, cellular aging involves changes in multiple gene pathways, which can produce many aging phenotypes. In the liver, senescence changes lead to impaired hepatic function. We hypothesized that the natural hepatic aging process is driven by sex-dependent mechanisms. Purpose: We studied our well-established model of aging in which we have previously determined aging of metabolism, reproduction and endocrine systems. We performed liver transcriptomics (RNA-seq) on male and female rats at 110 and 650 days (d) fed with normal rat chow to determine changes key signaling pathways related to senescence processes. Methods: To identify the functional F1 liver changes due to natural aging processes, we evaluated the differentially expressed genes (DEGs) between 650d and 110d in males and females, with separate pairwise comparisons due to the marked differences. Genes were filtered based on ?1.4 fold change (FC) and nominal P value <0.05 (Studentｴs t-test). Results: We found that the natural liver aging process shows sex-differences. RNA-seq revealed more male (3,967) than female (283) differentially expressed genes (DEG) and pathways over the 110d to 650d period studied. Cell cycle pathway signaling in males was accompanied by decreased protein and gene expression of key genes (CDK2, CDK4, Cycd and PCNA) and an increase of p57 at 650d vs. 110d. In females, protein and gene expression of cell growth regulators such as p15 and p21, that inhibit cell cycle G1 progression were increased. Moreover, additionally the cell senescence pathway showed sexual dimorphism in liver gene regulation. Conclusions: Our results demonstrate how the natural aging process affects the liver transcriptome signature in a sex-dependent manner, specifically in cell cycle and cell senescence pathways, pathways that contribute in a major fashion to the development of aging-induced liver diseases. Understanding cellular senescence pathways involved in the natural aging process will aid evaluation of mechanisms associated with altered aging and frailty trajectories.

Dataset Information

Distinct endothelial pathways underlie sexual dimorphism in vascular auto-regulation.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Distinct endothelial pathways underlie sexual dimorphism in vascular auto-regulation.

Similar Datasets

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