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


METHODS
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.


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.


CONCLUSIONS
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 K(Ca) channel activation, and (2) by an endothelium-independent mechanism involving H2O2 and subsequent activation of sGC.
Gao
Y-J
YJ
Department of Anesthesia, Smooth Muscle Research Program, McMaster University, Hamilton, Ontario, Canada. gaoyu@mcmaster.ca
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D000273:Adipose Tissue / Q000378:metabolism / Q000502:physiology*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000098:blood supply / Q000378:metabolism / Q000502:physiology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000494:pharmacology; D019789:Tetraethylammonium / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects
D000316:Adrenergic alpha-Agonists; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D010656:Phenylephrine; D019335:Nitroarginine; D012701:Serotonin; D019789:Tetraethylammonium; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase