| Description |
Using pharmacological and genetic approaches to inhibit whole-body ceramide biosynthesis, our laboratory showed that this sphingolipid contributes importantly to hypertension and vascular dysfunction associated with diet-induced obesity in mice. Here we tested the hypothesis that inducible, endothelial cell (EC) specific depletion of the rate-limiting enzyme responsible for ceramide biosynthesis, i.e., serine palmitoyl transferase light chain 2 (Sptlc2), preserves arterial function in obese mice. Six-week old male mice consumed standard (CON) or high-fat (HF) diet for 14-weeks. After 12-weeks on diet all mice were treated (P.O.) with tamoxifen. Tamoxifen induces EC-specific Sptlc2 deletion in mice harboring the VE-Cadherin cre promoter (Sptlc2KOiEC mice) but is without effect in VE-Cadherin cre negative mice (wild type; WT). After 14 weeks, mice completed metabolic and vascular phenotyping. qPCR results indicated Sptlc2 was depleted > 80% in carotid artery ECs but not vascular smooth muscle cells from CONSptlc2KOiEC vs. CON-WT mice. Preliminary results from: (i) glucose, insulin, and pyruvate tolerance tests; (ii) body composition analyses using NMR; and (iii) femoral artery vascular function analyses using isobaric procedures, indicate no differences exist between CON-Sptlc2KOiEC and CON-WT mice. Additional preliminary findings indicate that EC-specific Sptlc2 deletion does not impact the severity of metabolic or vascular dysfunction evoked by HF diet. For example: (i) glucose, insulin, and pyruvate tolerance tests; (ii) body composition analyses; (iii) non-receptor mediated vasocontraction to potassium chloride, receptor-mediated vasocontraction to phenylephrine, endotheliumdependent vasodilation to acetylcholine, and endothelium-independent vasodilation to sodium nitroprusside, were similar in femoral arteries from HF-Sptlc2KOiEC and HF-WT mice. Collectively, these preliminary data do not support our original hypothesis that ECspecific Sptlc2 deletion preserves arterial function in the context of diet-induced obesity. |
