Endothelium‐dependent relaxation is markedly decreased in LE2KO fed HFHSD. (A, B) Vascular relaxation of aortic rings with ACh (C) (controls on NC; n=10, LE2KO on NC; n=10, controls on HFHSD; n=9, LE2KO on HFHSD; n=9) and SNP (D) (controls on NC; n=8, LE2KO on NC; n=8, controls on HFHSD; n=10, LE2KO on HFHSD; n=10) on NC or HFHSD for 20 weeks, respectively. Results of relaxation are expressed as percentage changes in steady‐state level of contraction with 10−6.5 mol/L phenylephrine. (C) A representative western blot and quantification of phospho‐eNOS (Ser 1177)/ eNOS (n=6 for each group). Error bars represent SEM. *P<0.05, **P<0.01 vs. controls fed HFHSD. ACh indicates acetylcholine; ERK, extracellular signal‐regulated kinase; HFHSD, high‐fat/high‐sucrose diet; LE2KO, liver‐specific ERK2 knockout mice; NC, normal chow; SNP, sodium nitroprusside.