β ₃ -adrenergic receptor agonism blunts sympathetic vasoconstriction in healthy young females

Objective: Females are historically underrepresented in cardiovascular research; as a result, therapeutic approaches are derived from primarily male cohorts, leading to less effective treatments. Vascular β-adrenergic receptors (ARs) mediate blood flow and blood pressure responses to sympathetic nervous system activation. Preclinical studies show greater vascular β 3 -AR expression as well as enhanced β 3 -AR vasorelaxation in female compared to male rodents, indicating a unique potential for β 3 -ARs to modulate blood flow in females. We hypothesized pharmacological activation of β 3 -ARs would attenuate the peripheral vasoconstrictor response to acute sympathetic nervous system activation in healthy young females. Methods: Ten young healthy female participants (27±7 yr, 25±3 kg/m 2 ) completed two study visits randomized and blinded to oral placebo or Vibegron (75mg; a β 3 -AR agonist). On each visit, participants completed a 5-min quiet rest followed by a 2-min cold pressor test (CPT) to achieve sympathetic activation. Forearm blood flow (FBF, venous occlusion plethysmography) and blood pressure (BP, finger photoplethysmography) were assessed. FBF was normalized for mean BP (forearm vascular conductance, FVC) and reported as both absolute values and relative (%) changes from baseline. Results: On the placebo visit, sympathetic activation with CPT elicited robust decreases in absolute FBF (2.0±1.1 to 1.6±0.9 mL/dL/min; p=0.003) and FVC (2.4±1.3 to 1.7±1.1 mL/dL/min/100mmHg; p=0.001), confirming vasoconstriction with increased sympathetic activity. In contrast, the FBF (3.0±1.8 to 2.8±1.7 mL/dL/min; p=0.396), but not FVC (3.6±2.1 to 3.0±1.8 mL/dL/min/100mmHg; p=0.037), response to CPT was lost following β 3 -AR agonism with Vibegron. When compared to placebo, Vibegron attenuated CPT-mediated relative reductions in FBF (-21.2±16.7 to -0.3±23.0%, p=0.016) and FVC (-27.3±17.4 to -11.2±18.6%, p=0.021). Conclusion: Cardiovascular research has long centered on male cohorts, leaving gaps in knowledge about female physiology and limiting the efficacy of existing treatments. Herein we show β 3 -AR agonism with Vibegron attenuates the vasoconstrictor response to acute sympathetic nervous system activation in young healthy females. These preliminary data indicate β 3 -ARs are capable of restraining sympathetic-mediated vasoconstriction in females. Based on the known role of estrogen in mediating β-AR signaling, future work will investigate the impact of menopause and estrogen loss on this response. AHA 909014 (DWJ), HL153523 (JKL), University of Missouri Research Council (NGB, BPB, JKL) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.