Introduction There is considerable evidence to implicate over-activity of the sympathetic nervous system during obesity and the subsequent development of metabolic syndrome and type 2 diabetes. It has been suggested that these conditions are dependent upon changes in small artery function. Healthy perivascular fat exerts an anti-contractile effect on circulation which is lost in obesity. Therefore it was decided to examine the effects of sympathetic nerve stimulation on perivascular adipose tissue (PVAT) function. The hypothesis to be tested was that an anti-contractile factor is released from PVAT as a result of sympathetic nerve stimulation.
Methods The frequency-stimulation profiles (0.1–30 Hz) of murine mesenteric arteries (<200 µM), +/-PVAT, were characterised using wire myography at various voltages (5–30 V). The accepted test for neural stimulation using 1 µM tetrodotoxin (TTX) was performed, and 1.46 µM 6-hydroxydopamine (6-OHDA) used to sympathetically denervate vessels +/-PVAT. Exogenous PVAT was incubated with TTX and 6-OHDA for 30 min before re-suspending in the bath. Specific adrenoceptor stimulation of PVAT function was investigated using noradrenaline, phenylephrine (both 1 × 10–9–1 × 10–5M), and CL-316,243 (10 µm).
Results At 20&30V PVAT elicited an anti-contractile effect (P < 0.01); reproducible at 20V after a 15 min rest period. This effect is due to factors released from the PVAT and not due to a “barrier” effect, as application of exogenous PVAT elicits the same anti-contractile response (P < 0.05). Sympathetic denervation of whole vessels with 6-OHDA abolished all significant contractile activity, confirming that EFS at 20V innervates sympathetic nerves (P < 0.0001). PVAT incubated with TTX, demonstrated a reduced anti-contractile effect, confirming this effect to be neural and therefore physiologically relevant (P < 0.05). Exogenous PVAT pre-incubated with 6-OHDA also induced a diminished PVAT anti-contractile effect, implicating the role of sympathetic nerves in PVAT (P < 0.0001). In the noradrenaline but not phenylephrine concentration-response curve, PVAT elicits an anti-contractile response. The addition of β3-adrenoceptor agonist CL-316,243 to phenylephrine-constricted +PVAT vessels induced a relaxation which replicated the PVAT anti-contractile effect seen in vessels stimulated with NA (P < 0.05), indicating the role of β3-adrenoceptors in PVAT.
Conclusions These results clearly demonstrate sympathetic nerve stimulation can provoke the release of vasodilators from PVAT. The mechanism appears to be via activation of the adipocyte membrane located β3-adrenoreceptor. Further studies will be carried out in an obese model to understand how over-stimulation leads to a down-regulation and a loss of anti-contractility possibly via β3 receptor desensitisation.
- Perivascular adipose tissue
- Sympathetic nerves
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