Healthy perivascular adipose tissue (PVAT) exerts an anti-contractile effect on resistance arteries which is vital in regulating arterial tone. Activation of β3- adrenoceptors by the neurotransmitter, noradrenaline, may be implicated in the anti-contractile effect of PVAT. Accordingly, we have investigated the effect of sympathetic nerve stimulation (SNS) within PVAT on the anti-contractile effect, and have identified the mechanisms involved.Design and method:
Electrical field stimulation (EFS) profiles of murine mesenteric arteries (<200 μm, +/-PVAT) were characterised using wire myography (0.1–30 Hz, 20 V, 0.2ms pulse duration, 4 s train duration). To demonstrate the release of an anti-contractile factor, the solution surrounding stimulated exogenous PVAT was transferred to a PVAT denuded vessel. Neural inhibition using tetrodotoxin (TTX, 1 μM), or sympathetic denervation using 6-hydroxydopamine (6-OHDA, 2 μM) were performed. β3-adrenoceptor function was investigated using the agonist CL-316,243 (10 μM) and antagonist SR59203A (100 nM). Noradrenaline transport was studied using nisoxetine (1 μM) and corticosterone (100 μM).Results:
During EFS PVAT elicits a reproducible anti-contractile effect, which is replicated using exogenous PVAT. Solution transfer from stimulated exogenous PVAT to a –PVAT vessel significantly reduced contraction, confirming that stimulated PVAT releases a transferable anti-contractile factor. Neural inhibition using TTX, or sympathetic denervation with 6-OHDA, abolished all anti-contractile activity implicating sympathetic nerves in release of anti-contractile factors. β3-adrenoceptor agonist CL-316,243 enhanced the anti-contractile effect, and β3-adrenoceptor antagonist SR59203A reduced the anti-contractile effect, although the PVAT remains overall anti-contractile. Inhibition of all noradrenaline re-uptake using nisoxetine exhibited the same results as SR59230A, as did inhibition of the specific noradrenaline transporter; organic cation transporter-3 (OCT-3) using corticosterone. Combination of nisoxetine or corticosterone with SR59230A totally abolished the anti-contractile effect. Complete inhibition of the effects of the solution transfer could be achieved by incubation of exogenous PVAT with SR59203A.Conclusions:
These results demonstrate that SNS in PVAT elicits an anti-contractile effect by activation of adipocyte β3-adrenoreceptors, triggering the release of vasodilators, and by transport of noradrenaline back into nerves or adipocytes via OCT-3. This suggests that during SNS, healthy PVAT modulates the effects of noradrenaline. Loss of this function may contribute to the development of hypertension.