Beta3-adrenergic receptors and cardiovascular function in aging women

About This Grant

PROJECT SUMMARY/ABSTRACT The sympathetic nervous system is the major regulator of vascular tone. Activity of the sympathetic nervous system increases with age and directly contributes to vascular dysfunction. Norepinephrine released from sympathetic nerve terminals binds vascular α-adrenergic receptors (AR), promoting vasoconstriction and opposing endothelial-mediated vasodilation. Notably, β-AR mediated vasodilation attenuates sympathetic vasoconstriction in young women but not men – eliciting sex-specific vascular protection. Unfortunately, β-AR protection appears lost in women post-menopause. Herein we propose a personalized approach to preserve and restore vascular β-adrenergic receptor (AR) signaling and, in turn, reduce CVD risk in aging women. Our comprehensive experimental approaches will allow us to challenge current thinking as it relates to CVD risk during menopause by addressing a new and unexplored mechanistic and therapeutic option. Our study is framed in the context of the following aims and testable hypotheses: 1) Determine whether acute β3- AR agonism attenuates sympathetic vasoconstriction in aging women. We hypothesize acute treatment with the β3-AR agonist, vibegron (FDA-approved for urinary incontinence), attenuates sympathetic vasoconstriction in aging women as assessed by: a) the vasoconstrictor response to the cold pressor test, b) sympathetic vascular transduction. 2) Determine whether acute β3-AR agonism augments vascular function in aging women. We hypothesize acute treatment with the β3-AR agonist, vibegron, enhances vascular endothelial function in aging women, as assessed by flow mediated dilation (FMD). 3) Characterize vascular endothelial β3-AR expression in aging women. We hypothesize vascular endothelial β3-AR expression, assessed from venous endothelial cells collected from human volunteers, is maintained in aging women. Results of the proposed studies will uniquely determine the direct and modulatory effect of β3-AR on women’s vascular health. If successful, our findings will reveal a potential new area of investigation from which to enhance both mechanistic and therapeutic understanding as it relates to women’s CVD risk.