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

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 ( K-Ca). 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).