In smooth muscle cells (SMCs), caveolin (cav)-1, an essential component of caveolae, forms Ca²⁺ microdomain accumulating voltage-dependent Ca²⁺ channels (VDCC) and ryanodine receptors (RyR). The functional coupling between VDCC and RyR (Ca²⁺-induced Ca²⁺ release: CICR) causes SMC contraction, i.e. excitation-contraction (E-C) coupling. On the other hand, Ca²⁺ influx through VDCC activates Ca²⁺/calmodulin-dependent protein kinase, and promotes gene transcription in neurons, i.e. excitation-transcription (E-T) coupling. E-T coupling is known in SMCs, but its structural basis and physiologic function are unknown. Therefore, we examined the relationships between Ca²⁺ microdomain formed by caveolae and E-T coupling in SMCs. When the mesenteric artery was depolarized, the phosphorylation of CREB was detected in the nuclei of SMCs. This response was not observed in tissues from cav-1 KO mice that lack caveolae in SMCs and those in which caveolae were destroyed by methyl beta cyclodextrin. Inhibition of RyR by tetracaine also reduced the CREB phosphorylation. These results suggest that CICR in caveolae is necessary for the E-T coupling in SMCs. Caveolae can control not only SMC contractility but also gene expression by regulating Ca²⁺ signaling.