Objectives: 

Urotensin-II (UII) is a vasoactive peptide which promotes vascular smooth muscle cell (SMC) proliferation that contributes to vascular remodeling. Neverthless, the precise mechanism activated downstream of its receptor UTS2R remains elusive. The aim of this study was to determine the role of store operated Ca2+ entry (SOCE) in UII induced VSMC proliferation and in the activation of Ca2+/cAMP response element-binding (CREB), a transcription factor that regulates expression of many genes activated by Ca2+-induced phosphorylation.

Materials: 

We used a primary culture of SMC isolated from rat aorta and imaging system to investigate intracellular Ca2+ mobilization evoked by UII. SMC proliferation was determined by 5-bromo-2-deoxyuridine (Brdu) assay. CREB activation was also evaluated with immunofluorescence assay.

Results: 

UII application to SMC induced intracellular Ca2+ increase that was significantly reduced by classical SOCE inhibitors gadolinium (Gd3+), 2-aminoethoxydiphenyl borate (2APB), and ML-9. Moreover, knockdown of either STIM1, Orai1, and TRPC1, identified as essential components for the SOCE in different cells type inhibited significantly UII-induced Ca2+ entry. In addition, we observed that UII addition to SMC culture evoked CREB phosphorylation and promoted SMC proliferation. Both events were sensitive to SOCE inhibitors and to molecular downregulation of STIM1, Orai1, and TRPC1.

Conclusions: 

Our data determined that aortic VSMC proliferation require Ca2+ entry through a molecular macrocomplex signaling pathway, which depend on STIM1, Orai1 and TRPC1 possible associations.