Trimethylamine N‐Oxide (TMAO) Impairs Endothelium‐Dependent Relaxation in Mouse Mesenteric Resistance Artery and Aorta

Abstract

Trimethylamine N‐oxide (TMAO) is a gut microbiota‐dependent metabolite produced from choline and phosphatidylcholine and it has been related to risk for cardiovascular diseases. Studies have shown that increased levels of TMAO are associated with heart attack, stroke and heart failure. This study tested the hypothesis that TMAO has a deleterious effect on the vascular beds leading to vascular dysfunction. Sixteen‐week old male lean mice were euthanized and the aorta and mesenteric resistance arteries (MRA) were mounted in a wire myograph. Concentration response curves to acetylcholine (ACh; 0.001 – 30 μM), A23187 (0.1 – 10 μM) and sodium nitroprusside (SNP; 0.001 – 1 μM) were performed in the absence or in the presence of TMAO (100 μM – incubated for 30 min) in order to evaluate endothelium dependent and independent‐relaxation of the aorta and MRA. In the aorta, TMAO decreased the potency of ACh (pEC50: 7.96 ± 0.22 versus 7.25 ± 0.16) and EMAX to ACh (89 ± 06% versus 63 ± 4%). Similarly, potency to ACh was decreased by TMAO in the MRA (pEC50: 7.52 ± 0.43 versus 6.01 ± 0.15, with vs. without TMAO, respectively). TMAO did not alter endothelium‐dependent relaxation induced by the calcium ionophore A23817 in the MRA, but completely abolished the relaxation in the aorta. Endothelium‐independent relaxation elicited by SNP was not affected by incubation with TMAO in aortic rings, whereas it caused a significant decrease in the maximal response to SNP in the MRA. In conclusion, TMAO leads to endothelial dysfunction in aorta and MRA and impaired smooth muscle relaxation of the MRA which might contribute to the development of cardiovascular diseases.Support or Funding InformationNIH: NL13604