Over the last couple of years it has become increasingly clear that the Notch signaling pathway plays a pivotal role in the development and homeostasis of the cardiovascular system. The rapid increase in the number of publications that focus on the role of Notch signaling in regulating vascular cell function both in vitro and in vivo reflects the degree of interest in understanding the role of this pathway in vascular homeostasis. An emerging paradigm suggests that developmental gene regulatory networks are often recapitulated in the context of phenotypic modulation, vascular remodeling and repair in adult vascular disease. Notch receptor-ligand interactions, in conjunction with vascular endothelial growth factor (VEGF) and components of the Hedgehog (Hh) signaling pathway have all been implicated in vascular morphogenesis and modeling of the embryonic vasculature. The presentation will focus on the specific role of a Hh/VEGF/Ang axis in controlling vascular smooth muscle cell (SMC) growth (proliferation and apoptosis) through regulation of Notch signaling [1-5]. Using dynamic in vitro cultures of SMC under flow and pressure and ligated murine carotid arteries in vivo to mimic vascular injury, the components of these pathways in dictating the vascular SMC response to bio-mechanical injury will be addressed. Collectively, data will provide an insight into the coordinate regulation of Notch by sonic hedgehog (shh) and VEGF-A in adult SMC and thus may represent a future novel therapeutic target for intervention in vascular proliferative disorders.