Role of AMPK in the anti-contractile effect of the perivascular adipose tissue

Introduction: 5’ AMP-activated protein kinase (AMPK) is a serine/threonine kinase with many integral physiological roles, including regulation of energy metabolism. AMPK is present in the three major components of the vasculature: smooth muscle (VSM), the endothelium and perivascular adipose tissue (PVAT) and is known to induce vasodilatation with both endothelium- and non endothelium-dependent pathways. Although it is known that PVAT can modulate vascular function through actions on the endothelium and the VSM, the contribution of AMPK within the PVAT to these effects is not known. Therefore, the aim of study is to investigate the role of AMPK in Anticontractile effect of the PVAT.

Methods and Results: Thoracic aortic segments from wild-type (Sv129) and α1AMPK knockout (KO) mice were denuded of endothelium and mounted on a wire myograph in the presence and absence of PVAT. The vasodilator responses to an AMPK activator (AICAR) and the AMPK-independent vasodilator cromakalim were assessed in rings precontracted with U46619. Results (expressed as mean ± SEM) were analysed using two-way ANOVA (Bonferroni post-hoc). Relaxation responses to AICAR or cromakalim in the Sv129 mouse were significantly enhanced in the presence of PVAT (Emax 59.0 ± 12.3% vs. 27.7 ± 2.8; n=7; p<0.05), an effect that was absent in vessels from KO mice (n=7) (Emax 21.6 ± 1.6% vs. 18.7 ± 4.0%; n=7; p=ns). A similar effect was seen with AICAR (data not shown). Furthermore, enhanced relaxation was observed in vessels from KO mice incubated with PVAT from Sv129 mice (46.3 ± 10.8% (n=6); p<0.05 vs KO PVAT (+)), whereas PVAT from KO mice had no effect on relaxation of vessels from Sv129 mice. A similar pattern was seen with AICAR (data not shown). Addition of conditioned medium from wild-type PVAT also enhanced the relaxation response to cromakalim whereas KO conditioned medium did not enhance relaxation (52.4 ± 10.32%; n=6 vs KO (25.2 ± 2.25%; n=6; p<0.05). Adipokine array demonstrated that adiponectin release was significantly reduced in the KO conditioned media (CM) in comparison with wild type CM. PVAT-enhanced relaxation was attenuated in the presence of adiponectin blocking peptide while globular adiponectin (1 µg/ml) restored the relaxation response in both wild type and KO vessels without PVAT.

Conclusion: PVAT enhances vascular relaxation and is a potent source of adipokines. AMPKα1 is crucial in mediating the anticontractile effect of PVAT since the effect was lost in knockout mice. Deficiency of AMPKalpha1 appears to reduce generation of adiponectin from the PVAT and this could underlie the lack of effect of KO PVAT on vascular relaxation Further investigations are currently in progress to define the role of AMPK in adiponectin release and/or action.