Angiotensin II (Ang II) is an oligopeptide of the renin-angiotensin system, and Ang II-induced vascular smooth muscle cell (VSMC) proliferation is an important pathophysiological process involved in atherosclerosis; however, the underlying mechanism remains unclear. Orai1 and Stim1 are the main components of store-operated Ca entry (SOCE), which has an important effect on VSMC proliferation. In the present study, we showed that Ang II-induced human coronary smooth muscle cell (HCSMC) proliferation was associated with increased calcium entry. The expression of Orai1, but not that of Stim1, was significantly upregulated in Ang II-treated HCSMCs. However, knockdown of Orai1 or Stim1 decreased HCSMC proliferation and SOCE activity in Ang II-treated HCSMCs. Orai1 was significantly downregulated in HCSMCs transfected with short interfering RNA (siRNA) against NOX2 or NF-κB. Transfection with siRNA against NOX2 or p65 also decreased Ang II-induced HCSMCs SOCE activation and proliferation. These findings suggested that Ang II upregulated Orai1 via the NF-κB and NOX2 pathways, leading to increased SOCE and HCSMC proliferation. The molecular factors mediating Ang II-induced SOCE upregulation are potential therapeutic targets for the prevention of Ang II-sensitive or Ang II-dependent HCSMC proliferation.Copyright © 2020. Published by Elsevier Inc.