Obesity increases prostanoid-mediated vasoconstriction and vascular thromboxane receptor gene expression

Abstract

Objectives  

Vasoconstrictor prostanoids have been implicated in abnormal vasomotion in atherosclerosis and hypertension.

Method  

Using lean and diet-induced obese mice, we investigated whether obesity affects vascular function or expression of genes involved in prostanoid action.

Results  

In lean C57BL/6J mice, at high concentrations acetylcholine caused endothelium-dependent contractions in the carotid artery but not in the aorta. Endothelium-dependent contractions to acetylcholine were blocked by the non-selective cyclooxygenase (COX) inhibitors indomethacin and meclofenamate, or a prostaglandin H₂/thromboxane A₂ receptor antagonist, but not by inhibitors of COX-2, thromboxane synthase or cytochrome P₄₅₀ monooxygenase. Obesity increased endothelium-dependent contractions to acetylcholine in the carotid artery, and prostanoid-mediated vasoconstriction was now present in the aorta. Similarly, contractions to endothelin-1 were largely blocked by meclofenamate and were increased in the aorta of obese mice. Real-time quantitative polymerase chain reaction analysis of the thromboxane receptor gene in the carotid artery revealed a robust upregulation in obese animals (18-fold, P< 0.05); in comparison, obesity had a less pronounced effect on thromboxane synthase (2.1-fold increase, P< 0.05), or preproendothelin-1 gene expression (4.2-fold increase, P< 0.05).

Conclusions  

These data demonstrate that obesity augments prostanoid-dependent vasoconstriction and markedly increases vascular thromboxane receptor gene expression. These changes are likely to promote the development of vascular disease, hypertension and thrombosis associated with obesity.