BETA3-ADRENOCEPTOR MEDIATED ADIPONECTIN SECRETION IS ESSENTIAL IN MODULATION OF VASCULAR TONE BY PERIVASCULAR ADIPOSE TISSUE

Abstract

Objective: Healthy perivascular adipose tissue (PVAT) exerts an anti-contractile effect which is vital in regulating blood pressure. Evidence suggests that sympathetic nervous stimulation of PVAT triggers activation of adipocyte beta3-adrenoceptors, and the subsequent release of the vasoactive adipokine adiponectin. In obesity plasma adiponectin is reduced, which may result in a loss of PVAT function and subsequent hypertension. Therefore we examined beta3-adrenoceptor and adiponectin function in the PVAT anti-contractile effect. Design and method: Body weight, blood pressure, and blood glucose were measured in control C57 mice, and adiponectin knockout (Adipo-/-) mice. Following sacrifice, electrical field stimulation (EFS) profiles of isolated C57 and Adipo-/- mesenteric and skeletal muscle resistance arteries (<250 μm, ± PVAT) were characterised using wire myography. Sympathetic denervation of PVAT using 6-hydroxydopamine (6-OHDA) was performed. Beta3-adrenoceptor function was investigated using the agonist CL-316,243 and antagonist SR59203A. The role of the adipokine adiponectin was examined using exogenous adiponectin and a blocking peptide for adiponectin receptor 1 (ABP). The concentration of adiponectin secretion upon EFS was measured using an ELISA kit. Results: Adipo-/- mice exhibit significant elevations in both blood pressure and blood glucose. During EFS of isolated ± PVAT arteries, mesenteric and skeletal muscle PVAT from C57 mice elicited an anti-contractile effect, which was absent in the Adipo-/-. Sympathetic denervation of both mesenteric and skeletal muscle PVAT abolished the anti-contractile effect. Inhibition of beta3-adrenoceptors in C57 mesenteric and skeletal muscle PVAT using SR59230A significantly reduced the anti-contractile effect, however activation of beta3-adrenoceptors in Adipo-/- PVAT using CL-316,243 did not restore function. Application of exogenous adiponectin to C57 mesenteric and skeletal muscle –PVAT arteries caused a significant vasodilation. In ± PVAT arteries, incubation with ABP significantly reduced the anti-contractile effect. Using an ELISA, adiponectin secretion from PVAT upon EFS was significantly reduced when incubated with SR59230A. Conclusions: These results demonstrate that upon sympathetic stimulation, PVAT from two different vascular beds releases adiponectin via activation of beta3-adrenoreceptors, exerting an anti-contractile effect on the blood vessels. In the absence of adiponectin PVAT anti-contractile function is lost, resulting in hypertension and hyperglycaemia, highlighting the importance of adiponectin in vascular function.