Modulation of vascular function by perivascular adipose tissue: the role of endothelium and hydrogen peroxide

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Background and purpose:Perivascular adipose tissue (PVAT) attenuates vascular contraction, but the mechanisms remain largely unknown. The possible involvement of endothelium (E) and hydrogen peroxide (H2O2) was investigated.Experimental approach:Aortic rings from Wistar rats were prepared with both PVAT and E intact (PVAT+E+), with either PVAT or E removed (PVAT-E+, or PVAT+E-), or with both removed (PVAT-E-) for functional studies. Nitric oxide (NO) production was measured.Key results:Contraction to phenylephrine and 5-HT respectively was highest in PVAT-E-, lowest in PVAT+E+, and intermediate in PVAT+E- or PVAT-E+. In bioassay experiments, transferring bathing solution incubated with a PVAT+ ring (donor) to a PVAT- ring (recipient) induced relaxation in the recipient. This relaxation was abolished by E removal, NO synthase inhibition, scavenging of NO, high extracellular K+, or blockade of calcium-dependent K+ channels (KCa). The solution stimulated NO production in isolated endothelial cells and in PVAT-E+ rings. In E- rings, the contraction to phenylephrine of PVAT+ rings but not PVAT- rings was enhanced by catalase or soluble guanylyl cyclase (sGC) inhibitor, but reduced by superoxide dismutase and tiron. In PVAT-E- rings, H2O2 attenuated phenylephrine-induced contraction. This effect was counteracted by sGC inhibition. NO donor and H2O2 exhibited additive inhibition of the contraction to phenylephrine in PVAT-E- rings.Conclusion:PVAT exerts its anti-contractile effects through two distinct mechanisms: (1) by releasing a transferable relaxing factor which induces endothelium-dependent relaxation through NO release and subsequent KCa channel activation, and (2) by an endothelium-independent mechanism involving H2O2 and subsequent activation of sGC.British Journal of Pharmacology (2007) 151, 323–331; doi:10.1038/sj.bjp.0707228

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