Epidermal growth factor receptor (EGFR) is activated by its canonical ligands and transactivated by various vasoactive substances, e.g. angiotensin II. Vascular EGFR has been proposed to be involved in vascular tissue homeostasis and remodeling. Thus, most studies focused on its role during long term vascular changes whereas the relevance for acute regulation of vascular function in vivo and ex vivo is insufficiently understood. To investigate the role of the EGFR in the vasculature, we generated mouse models with cell-specific deletion of the EGFR either in smooth muscle cells (VSMC) or endothelial cells (EC). The impact of the EGFR on vasoconstriction and vasodilation was analyzed by Mulvany myography and pressure myography. Aortic rings or mesenteric arteries were utilized respectively. In aortic rings dose response curves for angiotensin II (Ang II, 1-1000 nmol/l) were performed and vasoconstriction upon the application of a single dose U46619 (30 nM), a thromboxan analogue was tested. After preconstriction with U46619 vasorelaxation was analyzed by applying cumulative doses of carbachol (10-7-10-3 M) or S-Nitroso-N-acetyl- penicillamine (SNAP, 10-9-10-5 M). Preconstricted mesenteric arteries (U46619) were treated as described for aortic rings. Performing dose response curves to ang II the generation of force was significantly weaker by aortic rings from mice with deletion of the EGFR in VSMC. While the maximum response was about 3.5 mN for wildtype aortic rings, only 1 mN additional force could be generated by knockout aortic rings by application of 100 nM ang II. We hypothesize that the EGFR in VSMC inhibits the homologous desensitization of the AT1-receptor as repetitive application of ang II reduced the force generation in knockout aortic rings faster. Upon application of U46619 there was a similar increase in force generation by aortic rings with or without (w/o) deletion of the EGFR in VSMC. No difference in the response to carbachol or SNAP could be observed between aortic rings and mesenteric arteries from mice w/o deletion of the EGFR in VSMC. Force generation of aortic rings from mice w/o deletion of the EGFR in EC was the same in response to ang II and U46619. Additionally, the relaxation upon SNAP application was the same by aortic rings from wildtype and knockout animals, in contrast, relaxation towards carbachol was reduced in aortic rings as well as in mesenteric arteries from mice with deletion of the EGFR in EC. This indicates that the EGFR in EC inhibits the development of endothelial dysfunction. In conclusion: the EGFR in EC is needed for appropriate endothelial function but not the acute ang II vasoconstrictive response, while EGFR in vascular smooth muscle cells increases ang II response but is not necessary for endothelial function.