Endothelin-1- and depolarization-induced differential regulation of cAMP response element-binding protein in proliferating and developed vascular smooth muscle.

Regulation of the transcription factor cAMP response element-binding protein (CREB) is important for gene expression in vascular smooth muscle (VSM). This study has examined the intracellular regulation of CREB by endothelin-1 (ET-1) and depolarization in native VSM, comparing proliferative and fully differentiated phenotypes. Portal veins from neonatal (proliferative) and 6-week-old (differentiated) rats were stimulated with ET-1 or K(+). In both phenotypes, CREB activation was increased by ET-1 although the time course was prolonged in neonatal VSM. This paralleled a prolonged ET-1-induced [Ca(2+)](i) increase. ET-1-induced CREB activation was dependent on extracellular signal-regulated kinase 1/2 (ERK1/2) activation and inhibited by BAPTA but not by a calmodulin-dependent protein kinase (CamK) inhibitor. In contrast, CREB activation induced by depolarization in both neonatal and developed VSM was significantly reduced by CaMK inhibition and by ERK1/2 inhibition. Therefore, CREB activation is regulated differentially in VSM depending upon stimulus; however, this is not altered in different growth states.