Endothelin-1 Stimulates Small Artery VCAM-1 Expression through p38MAPK-Dependent Neutral Sphingomyelinase

Endothelin-1 (ET-1) stimulates vascular cell adhesion molecule (VCAM-1) expression, a process associated with arterial remodelling. However, the pathways activated by ET-1 that lead to VCAM-1 expression are not fully understood. It is reported that sphingomyelinases are necessary for VCAM-1 expression in response to cytokines. Our aim was to investigate the role of sphingomyelinases in ET-1-induced VCAM-1 expression. Acid and neutral sphingomyelinase activities were measured in extracts from rat mesenteric small arteries (RMSA). ET-1 (1-100 nmol/l) stimulated neutral but not acid sphingomyelinase. The activation was rapid, peaking within 5 min and transient, returning towards baseline by 10 min and inhibited by BQ-788, GW4869 and SB203580, which are inhibitors of ET(B) receptor, neutral sphingomyelinase and p38MAPK, respectively. Both GW4869 and SB203580 are reported to inhibit activation of neutral sphingomyelinase 2 implicating it in the response to ET-1. Accordingly we investigated the expression of this isoform and found it was present in RMSA, predominantly in endothelial cells. Treatment of RMSA with ET-1 (1-100 nmol/l) for 16 h increased VCAM-1 expression, which was inhibited by GW4869 and SB203580. These results indicate that ET-1 stimulates arterial VCAM-1 expression through p38MAPK-dependent activation of neutral sphingomyelinases. This suggests a role for sphingolipids in ET-1-induced vascular inflammation in cardiovascular disease.