Toll-like receptor 4 mediates the vasoconstrictor response initiated by adipose tissue in mice arteries

Abstract

Adipose tissue modulates vascular tone by secreting a number of pro-and anti-inflammatory cytokines including tumour necrosis factor-α (TNFα) and adiponectin, respectively. Toll-like receptor 4 (TLR4) is a major target for lipopolysaccharide and saturated fatty acids, both of which are potent inducers of inflammation. The present study investigated whether or not TLR4 mediates vascular dysfunction induced by obese adipose tissue. Aorta and carotid arteries from 12-week-old wild type mice on standard diet were isolated. White peri-aortic and epididymal adipose tissues from TLR4 mutant mice or wild type littermates fed a high fat diet (HFD) were dissected for ex vivo culture. Isometric tension was measured in artery rings in the absence or presence of conditioned medium collected from the fat explant culture. Several pro- and anti-inflammatory cytokines in adipose tissues were assayed by RT-quantitative PCR. In the presence of N(G)-nitro-L-arginine methyl ester (nitric-oxide synthase inhibitor), epididymal fat from wild type but not TLR4 mutant mice potentiated acetylcholine-mediated endotheliumdependent contraction in carotid arteries. Indomethacin (cyclooxygenase inhibitor) and S18886 (TP receptor antagonist) inhibited the contraction. In addition, inactivation of TLR4 restored the impaired anti-contractrile effect of perivascular fat in aorta caused by HFD feeding. These changes were associated with increased adiponectin expression, but decreased expression of TNFαand interleukin-6 in the adipose tissues of TLR4 mutant mice. Epididymal fat from obese mice facilitates endotheliumdependent contractions to acetylcholine through activation of TLR4, which in turn triggers the release of pro-inflammation cytokines. Perivascular fat from TLR4 mutant mice curtails the contraction possibly by increasing adiponectin.