Ceramide enhances COX-2 expression and VSMC contractile hyperreactivity via ER stress signal activation

Ceramide accumulation in blood vessels has been attributed to vascular dysfunction in progressive vascular complications in metabolic diseases. The present study showed that ceramide pretreatment promoted PE-induced vasoconstriction in rat endothelium-denuded vascular rings in a time- and dose-dependent manner. Endoplasmic reticulum (ER) stress inhibitors, 4-PBA and TUDCA, COX-2 inhibitors, Celecoxib and NS398, as well as PGE(2) receptor antagonist AH-6809 attenuated ceramide-promoted vascular hyperreactivity. Ceramide promoted the transcriptional and translational expression of COX-2 and BiP in VSMCs, which were blocked by the ER stress inhibitors, 4-PBA and TUDCA. These findings show that ceramide enhances PE-induced vascular smooth muscle constriction by mediation of the ER stress/COX-2/PGE(2) pathway. Therapeutic strategies targeted to reducing ER stress and COX-2 activation might be beneficial in attenuating vascular complications. Chemical compounds: C-2-Ceramide (N-acetyl-n-erythro-sphingosine) CID:2662 Tauroursodeoxycholic Acid Sodium (TUDCA) CID:9848818 phenylephrine (PE) CID:6041.