Abstract 11299: Adiponectin at Physiologically Relevant Concentrations Fails to Induce Direct Vasorelaxation but Regulates the Balance Between Other Endogenous Vasoconstrictors and Vasodilators via Cav-1/AdipoR-1 Signaling
The association between adiponectin (APN) and hypertension is evident in clinical studies, as hypoadiponectinema is an independent hypertension risk factor. Although supra-pharmacological APN causes direct vasodilation, the role of physiologic APN levels in vascular hemostasis remains unclear. The current study investigated the vaso-effect of physiologic APN concentrations upon Ang-II-induced vasoconstriction in mouse aortae. Consistent with previous reports, APN at supra-pharmacologic levels causes significant vasodilatation. However, physiologic APN concentrations (3-10 μg/ml) alone failed to cause significant arterial relaxation. Interestingly, pretreatment of aortae with physiologic APN levels significantly enhanced acetylcholine (ACh)-induced maximal vasodilatation (P<0.05) and decreased time to maximal vasorelaxation (P<0.05). A membrane-situated APN signalsome, containing APN receptor 1 (AdipoR1) and caveolin-1 (Cav-1), has been recently reported to facilitate APN signaling transduction. To evaluate whether the APN signalsome participates in the permissive effect of APN in agonist-induced vasorelaxation, genetic knockout mice were employed. Cav-1-KO virtually abolished ACh-induced vasorelaxation in the presence or absence of APN. However, AdipoR1-KO abolished APN-enhancement of Ach-vasorelaxation without altering the vasodilatory effect of ACh itself during Ang-II induced contraction. Mechanistically, treatment of human endothelial cells with physiologic APN concentrations caused significant eNOS phosphorylation and nitric oxide (NO) production, an effect abolished in AdipoR1-KD or Cav-1-KD cells. Taken together, these data demonstrate that although physiologic APN levels are insufficient to antagonize vasoconstriction caused by hypertensive mediators such as Ang-II, it enhances vasorelaxative response to vasodilatory factors (such as ACh) by inducing eNOS phosphorylation via AdipoR1/Cav-1 mediated signaling. Pathologic conditions impairing APN, such as diabetes and metabolic syndrome, may therefore instigate hypertension development. Therapies restoring APN may represent novel modalities preventing hypertension onset and its costly complications.
Author Disclosures: Y. Wang: None. J. Li: None. R. Li: None. G. Liu: None. W. Lau: None. Y. Yuan: None. T. Christopher: None. B. Lopez: None. X. Ma: None.
This research has received full or partial funding support from the American Heart Association
- © 2014 by American Heart Association, Inc.