The Epidermal Growth factor receptor (EGFR) is involved in regulation of cell proliferation, survival and differentiation. Pathophysiological effects of EGFR include e.g. parainflammatory dysregulation of tissue homeostasis. Beside the activation by its own ligands EGFR signalling can be induced by transactivation via like g-protein coupled receptors, for example endothelin receptor type A, a₁-adrenergic receptors. This mechanism has been proposed to contribute to GPCR-induced vasoconstriction. To investigate the functional importance of EGFR in VSMC we compared isometric force generation as response to different vasoactive stimuli in aortic rings from mice with targeted deletion of the EGFR (EGFR^D/DVSMC) and their littermate controls (EGFR^+/+VSMC). EGF-induced force generation was abolished in EGFR^D/DVSMC. The response to 25mM KCl was significantly reduced in aortic rings from EGFR^D/DVSMC. There was no difference in absolute force generation (mN) between the two genotypes upon stimulation with endothelin-1 (100 nM) or serotonin (10mM). When aortic rings where exposed to rising concentrations of noradrenaline, a significant increase in force occured in both genotypes. However, the increase was more pronounced in EGFR^D/DVSMC. Furthermore, stimulation with high NA concentrations (1 mM) leading to additional activation of b₂-AR, resulted in a significant force reduction in EGFR^+/+VSMC but not in EGFR^D/DVSMC. Additionally, NA-induced desensitization was observed only in aortae from EGFR^D/DVSMC. In conclusion, in VSMC EGFR per se exerts a slight vasoconstriction upon ligand binding. More importantly, EGFR modulates the vascular response to NA, thereby possibly preventing sympathetic stress under otherwise physiological conditions.