Abstract 19979: Rapid ERα-AMPK Signaling Stimulates Vasorelaxation via ERK-Mediated Pathway
Background: 17-β-estradiol has been shown to play an important role in regulating vascular function and vasomotor tone. We have previously demonstrated sex differences in rapid estrogen receptor signaling during vascular relaxation. We recently observed that estrogen activates AMPK-activated protein kinase (AMPK), suggesting that AMPK is a likely mediator of estrogen receptor (ER) signaling in vasomotor function. AMPK has been reported to participate in vascular relaxation. Furthermore, our recent studies found that incubating vascular rings with 5-aminoimidazole-4-carboxamide (AICAR), an AMPK activator, results in greater vasorelaxation of female C57BL/6J mouse vessels when compared with male vessels. However, the precise mechanisms involving estrogen receptor signaling and AMPK in promoting vascular relaxation remain unknown.
Methods and Results: To elucidate a critical role of ERα-AMPK signaling and downstream targets involved in vascular relaxation, including the potential sex difference in the influence of this signaling pathway, we conducted vessel tension studies in the aortas of 12-week-old male and female C57BL/6J mice. We analyzed male and female aortic rings preincubated with the ERα antagonist, MPP dihydrochloride and found that AICAR-stimulated relaxation was nearly abolished in both sexes. Next, we found that aortic rings preincubated with the extracellular signal-regulated kinase (ERK) inhibitor, PD98059 also dramatically attenuated AICAR-induced aortic relaxation in male and female vessels and eliminated the sex-related difference in vascular relaxation with AICAR. Finally, vessel contraction-relaxation studies with endothelium-denuded vessels demonstrated the functional significance of endothelial cells in AICAR-induced relaxation in both sexes. Removing the endothelial cell layer reduced AICAR-stimulated vascular relaxation and obviated the sex difference.
Conclusions: These experiments show the importance of ERα-AMPK-ERK signaling during vasomotor function in male and female mouse vessels and established the critical role of the endothelium in AICAR-induced vasorelaxation. Our findings implicate a sex-linked role of rapid ERα-AMPK-ERK signaling for the regulation of vascular tone.
Author Disclosures: S.C. Kim: None. M.H. Hamblin: None.
- © 2016 by American Heart Association, Inc.