The epidermal growth factor receptor (EGFR) plays an important role in vascular function. EGFR is involved in vasoconstrictive pathways as well as in hypertrophic scenarios. We generated a mouse model in which the EGFR is deleted in vascular smooth muscle cells (VSMC). Aortic VSMC were isolated from Wildtype (VSMC ^+/+EGFR), heterozygous (VSMC ^D/+EGFR) or knockout animals (VSMC ^D/DEGFR) and taken in culture up to passage 10. Protein content, cell death (apoptotic or necrotic), glucose-6-phosphate dehydrogenase (G6PD) activity and fibronectin or collagen formation were determined. Additionally, the responsiveness of the cells to EGF was studied. Protein content in VSMC ^D/DEGFR was reduced to 50% compared to VSMC ^+/+EGFR and to roughly 83% in VSMC ^D/+EGFR. This was accompanied by an increase in caspase-3 activity and LDH-release, indicating both apoptotic and necrotic cell death, respectively. In VSMC ^D/DEGFR G6PD activity was reduced to half compared to VSMC ^+/+EGFR or VSMC ^D/+EGFR. The formation of collagen III was increased 3-fold and that of fibronectin roughly 2-fold compared to VSMC ^+/+EGFR. In contrast to VSMC ^+/+EGFR, addition of EGF did not protect VSMC ^D/DEGFR from necrosis and had no activity-increasing influence on G6PD activity. These results indicate that VSMC lacking EGFR suffer at least partially from a decreased NADPH regenerating capacity possibly leading to apoptotic and necrotic cell death. This is accompanied by altered extracellular matrix generation which may contribute to vascular remodelling (supported by DFG: GE 905/14-1)