cAMP-response element-binding protein mediates prostaglandin F2α-induced hypertrophy of vascular smooth muscle cells

Prostaglandin F2α (PGF2α) is a vasoactive factor that causes constriction and hypertrophy of vascular smooth muscle cells (VSMCs). However, the mechanism of PGF2α-induced hypertrophy is largely unknown. Cyclic AMP-response element (CRE)-binding protein (CREB), the best characterized stimulus-induced transcription factor, activates transcription of target genes with CRE and promotes cell growth. We examined the role of CREB in PGF2α-induced hypertrophy of VSMCs. PGF2α induced phosphorylation of CREB at serine 133, which is a critical marker of activation, after 5-10 min of stimulation in a dose-dependent manner. Pharmacological inhibition of extracellular signal-regulated protein kinase and p38 mitogen-activated protein kinase (p38-MAPK) suppressed PGF2α-induced CREB phosphorylation. Inhibition of epidermal growth factor receptor (EGFR) and mitogen- and stress-activated protein kinase-1 also suppressed PGF2α-induced CREB phosphorylation. Overexpression of dominant-negative form of CREB (AdCREB M1), of which serine 133 was replaced with alanine, inhibited PGF2α-induced c-fos mRNA expression as well as hypertrophy of VSMCs [hypertrophy index (μg/104 cell); control 8.13, PGF2α 9.85, AdCREB M1 7.91, and AdCREB M1 + PGF2α 8.43]. These results suggest that PGF2α activated CRE-dependent gene transcription through EGFR transactivation, and the CREB pathway plays a critical role in PGF2α-induced hypertrophy of VSMCs.