Role of sympathetic nerves and adipocyte catecholamine uptake in the vasorelaxant function of perivascular adipose tissue.

Objective: Healthy perivascular adipose tissue (PVAT) exerts an anticontractile effect on resistance arteries which is vital in regulating arterial tone. Activation of β3 -adrenoceptors by sympathetic nerve-derived NA (noradrenaline) may be implicated in this effect and may stimulate the release of the vasodilator adiponectin from adipocytes. Understanding the mechanisms responsible is vital for determining how PVAT may modify vascular resistance in vivo. Approach and Results: Electric field stimulation profiles of healthy C57BL/6J mouse mesenteric resistance arteries were characterized using wire myography. During electric field stimulation, PVAT elicits a reproducible anticontractile effect, which is endothelium independent. To demonstrate the release of an anticontractile factor, the solution surrounding stimulated exogenous PVAT was transferred to a PVAT-denuded vessel. Post-transfer contractility was significantly reduced confirming that stimulated PVAT releases a transferable anticontractile factor. Sympathetic denervation of PVAT using tetrodotoxin or 6-hydroxydopamine completely abolished the anticontractile effect. β3 -adrenoceptor antagonist SR59203A reduced the anticontractile effect, although the PVAT remained overall anticontractile. When the antagonist was used in combination with an OCT3 (organic cation transporter 3) inhibitor, corticosterone, the anticontractile effect was completely abolished. Application of an adiponectin receptor-1 blocking peptide significantly reduced the anticontractile effect in +PVAT arteries. When used in combination with the β3-adrenoceptor antagonist, there was no further reduction. In adiponectin knockout mice, the anticontractile effect is absent. Conclusions: The roles of PVAT are 2-fold. First, sympathetic stimulation in PVAT triggers the release of adiponectin via β3 -adrenoceptor activation. Second, PVAT acts as a reservoir for NA, preventing it from reaching the vessel and causing contraction