Ceramide evokes vascular dysfunction independent of effects on insulin sensitivity and glucose homeostasis

Dihydroceramide desaturase (des1) is an enzyme required for ceramide synthesis. To explore whether ceramide contributes to vascular dysfunction in mice with diet‐induced obesity (DIO), 7‐week old mice with genetic ablation of one allele of des1 (i.e., des1+/−) and wild type littermates (i.e., des1 +/+) consumed chow that contained 10% (CON) or 45% fat (HF; n=9 per group). At 19 weeks body mass, fat mass and area under the curve during a glucose tolerance test (AUC) were greater (p<0.05) in HF vs. CON mice, regardless of genotype. Ceramide (ng ceramide/mg aorta) increased (p<0.05) from 47±4 (CON) to 78±5 (HF) in des1 +/+ mice, but was similar between CON (54±4) and HF (38±2) des1+/− mice. Endothelium‐dependent and –independent relaxation of femoral arteries (~ 190 um i.d.) was assessed with acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, using isometric tension techniques (18–20 vessels per group). As anticipated, ACh‐mediated (10 −8 , 2×10 −8 , and 3×10 −8 M) relaxation was less (p<0.05) in HF des1 +/+ (6±2%, 21±3%, and 33±4%, respectively) vs. CON des1 +/+ mice (21±4%, 41±6%, and 52±6%, respectively). As hypothesized, % vasorelaxation to ACh was similar in arteries from HF and CON des1+/− mice. Vascular smooth muscle function was intact in all groups. Thus, arterial ceramide accumulation contributes directly to endothelium‐dependent dysfunction in mice with DIO. NIHR15HL091493, ADA7‐08‐RA‐164