No abstract

Several clinical and large population studies indicate that women are more salt-sensitive than men, yet the precise mechanisms by which the sexually dimorphic onset manifests remains incompletely understood. Here, we evaluate recent epidemiological data and highlight current knowledge from studies investigating sex-specific mechanisms of salt-sensitive blood pressure (SSBP). Emerging evidence indicates that women of all ethnicities are more salt-sensitive than men, at all ages both premenopausal and postmenopausal. However, menopause exacerbates severity and prevalence of SSBP, suggesting that female sex chromosomes predispose to and female sex hormones mitigate SSBP. Results from both human and rodent studies support the contribution of enhanced and inappropriate activation of the aldosterone-ECMR (endothelial cell mineralocorticoid receptor) axis promoting vascular dysfunction in females. Increases in adrenal response to angiotensin II, in association with higher ECMR expression and activation of endothelial ENaC (epithelial sodium channel) in females compared to males, are emerging as central players in the development of endothelial dysfunction and SSBP in females. Female sex increases the prevalence and susceptibility of SSBP and sex hormones and sex chromosome complement may exert antagonistic effects in the development of the female heightened SSBP.

All smooth muscle cell (SMC) restricted Cre mice recombine floxed alleles in vascular and visceral SMCs. We generated a new tamoxifen-inducible CreERT2 mouse, Itga8-CreERT2, and compared its activity to the widely used Myh11-CreERT2 mouse. Both CreERT2 mice showed similar activity in vascular SMCs; however, Itga8-CreERT2 displayed limited activity in visceral SMC-containing tissues (e.g., intestine). Myh11-CreERT2 (but not Itga8-CreERT2) mice displayed high levels of CreERT2 protein, tamoxifen-independent activity, and an altered transcriptome. Whereas Myh11-CreERT2-mediated knockout of Srf resulted in a lethal intestinal phenotype, loss of Srf with Itga8-CreERT2 (SrfItga8) revealed viable mice with attenuated vascular SMC contractile gene expression, but no evidence of intestinal pathology. Male and female SrfItga8 mice presented with vascular contractile incompetence; however, only male SrfItga8 mice showed systemic changes in blood pressure. These results establish the Itga8-CreERT2 mouse as an alternative to existing SMC Cre strains, including Myh11-CreERT2, where SMC gene loss results in visceral myopathies that obfuscate accurate phenotyping in vascular SMCs.

No abstract

Obesity, which is a major risk factor for hypertension and cardiovascular disease, abolishes the cardioprotective effects of female sex hormones and predisposes women to hypertension. Although 40% of postmenopausal women are obese and 75% are hypertensive, the mechanisms whereby obesity and menopause interact to elevate blood pressure (BP) remains unknown. Formerly, our laboratory demonstrated that hypertension involves leptin‐mediated increases in aldosterone production in obese female mice of reproductive age. Herein, we hypothesized that loss of female sex hormones with ovariectomy (OVX) will further elevate BP and impairs vascular function in obese female mice. Obese agouti yellow mice (Ay) on a KK background and lean controls underwent OVX or sham surgery at 12‐week of age. At 15 weeks, mice were implanted with radiotelemeters to record BP under baseline conditions and in response to leptin receptor blockade (Allo‐Aca, 0.05mg/kg/day s.c. osmotic minipump). To ascertain the effects of OVX on autonomic control of BP, we recorded BP and heart rate (HR) responses to ganglionic blockade (hexamethonium), atropine, and propranolol. At 18 weeks, mice were euthanized and mesenteric arteries isolated to measure endothelial function via wire myography. Obesity significantly increased mean arterial pressure (MAP), systolic BP, diastolic BP, and HR but OVX did not further elevate BP. Interestingly, obesity also disrupted circadian rhythm. Unexpectedly, OVX significantly reduced MAP response to ganglionic blockade (2‐way ANOVA, P<0.05) in obese mice but preserved HR responses to propranolol and atropine respectively suggesting lower neurogenic control of BP. Allo‐Aca treatment significantly decreased (2‐way ANOVA, P<0.05) MAP in both sham and OVX obese mice, indicating BP elevation remains leptin‐dependent. Obesity significantly impaired relaxation to acetylcholine (2‐way ANOVA, P<0.05) but OVX did not further impair relaxation. Compared to lean controls, LNAME further reduced (2‐way ANOVA, P=0.054) relaxation responses to acetylcholine in obese OVX mice suggesting greater contribution of nitric oxide synthase activity to vascular relaxation. Quantitative real‐time PCR showed a trend for decreased adrenal aldosterone synthase (CYP11B2) expression in obese OVX mice. Interestingly, menopause induced a similar decrease in CYP11B2 expression in human adrenal tissue collected from kidney donors with elevated BMIs (postmenopausal 56 yo female: BMI 27.4, vs. premenopausal 43 yo female, BMI 32). Quantification of mouse plasma aldosterone levels via LC‐MS revealed no significant difference in circulating aldosterone levels, suggesting that tissue(s) other than the adrenals could potentially produce aldosterone in obese OVX mice. Plasma analysis also revealed Allo‐Aca treatment increased ANG II, ANG I and ANG 1‐7 in obese mice. In conclusion, these data suggest that obesity‐associated hypertension remains leptin dependent in the absence of female sex hormone and that female sex steroids play limited role in the control of the devel...