Salt Sensitivity of Blood Pressure in Women.

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.

Generation and Comparative Analysis of an Itga8-CreER T2 Mouse with Preferential Activity in Vascular Smooth Muscle Cells.

All current smooth muscle cell (SMC) Cre mice similarly recombine floxed alleles in vascular and visceral SMCs. Here, we present an Itga8-CreER T2 knock-in mouse and compare its activity with a Myh11-CreER T2 mouse. Both Cre drivers demonstrate equivalent recombination in vascular SMCs. However, Myh11-CreER T2 mice, but not Itga8-CreER T2 mice, display high activity in visceral SMC-containing tissues such as intestine, show early tamoxifen-independent activity, and produce high levels of CreERT2 protein. Whereas Myh11-CreER T2 -mediated knockout of serum response factor (Srf) causes a lethal intestinal phenotype precluding analysis of the vasculature, loss of Srf with Itga8-CreER T2 (Srf Itga8 ) yields viable mice with no evidence of intestinal pathology. Male and female Srf Itga8 mice exhibit vascular contractile incompetence, and angiotensin II causes elevated blood pressure in wild type, but not Srf Itga8 , male mice. These findings establish the Itga8-CreER T2 mouse as an alternative to existing SMC Cre mice for unfettered phenotyping of vascular SMCs following selective gene loss.