Aim To study the effect of calcineurin (CaN)-dependent signaling passway on proliferation of rat vascular smooth muscle cells(VSMC) under stimulation of Ryanodine (RY). Methods Upon the model of cultured rat VSMC, Ca 2+ releasing from Ca 2+ stores stimulated with RY, CaN signaling pathway was blocked with cyclosporine A (CsA) and Ca 2+ channel with verapamil(Ver), detecting the activities of VSMC CaN, mitogen activated protein kinase (MAPK) and protein kinase C(PKC), 3 H-Leucine( 3 H-Leu) and 3 H-Thymidine( 3 H-TdR) incorporation as the target to evaluate VSMC proliferation. Results Synthesis rate of protein and nucleic acid stimulated by RY in VSMC increased significantly in contrast to control (P<0.01); CsA and Ver markedly inhibited syntheses of protein and nucleic acid mediated by RY in VSMC with a significant difference from RY-stimulated group(P<0.01). CsA and Ver also suppressed VSMC CaN activity mediated by RY, and Ver suppressed VSMC PKC activity mediated by RY. Conclusions The study indicates CaN signaling pathway play an important role in VSMC proliferation induced by RY, but it is not the only signaling pathway in regulating VSMC proliferation, MAPK-centered signaling pathway is also involved in VSMC proliferation induced by RY.