Vascular Smooth Muscle Cell (SMC) fate decisions are fundamental features in the pathogenesis of vascular disease. We investigated the role of Notch 1 and 3 receptor signalling in controlling adult rat SMC growth in vitro. Constitutive expression of active Notch receptors, Notch 1 IC. and Notch 3 IC, resulted in significant upregulation of CBF-l/RBP-Jk-dependent promoter activity and Notch target gene expression concomitant with significant increases in SMC growth. Moreover, inhibition of endogenous Notch mediated CBF-l/RBP-Jk regulated gene expression resulted in a significant decrease in cell growth. Furthermore we examined the specific role of a Hedgehog (Hh)/vascular endothelial growth factor (VEGF) pathway in controlling vascular SMC growth through regulation of Notch signalling. We determined that Hh signalling pathway components are constitutively expressed VSMC in culture. Moreover activation of Hh signalling with recombinant Shh resulted in a significant increase in Hh signalling concomitant with an increase in VEGF expression, cell growth and activation of Notch target gene expression in SMC. Inhibition of Hh signalling with cyclopamine resulted in a decrease in Hh signalling concomitant with a decrease in SMC growth while concurrently decreasing Notch target gene expression. Moreover, Shh-mediated stimulation of SMC growth was significantly attenuated following inhibition of Notch target gene expression. In addition, we investigated the role of cyclic strain in modulating Notch/Hh mediated growth of SMC in vitro. Rat SMC cultured under the condition of cyclic strain exhibited a temporal and force dependent reduction in Notch and Hh signalling concomitant with a decrease in SMC growth. Furthermore we could reverse this downregulation of Notch/Hh signalling and subsequent decrease in SMC growth by over-expression of Notch 3 IC .To validate these finding we utilized two in vivo models of increased biomechanical forces and vascular remodelling where we determined that altered mechanical forces significantly downregulate Notch/Hh signalling concomitant with decreased growth in vivo. Collectively, these data suggest that Hh control of SMC fate via VEGF activation of Notch may represent a novel therapeutic target for disease states in which changes in vascular cell fate occur.