The novel findings of this study include the following: (a) ERK signalling is not synergistic with canonical TGF‐β signalling with regard to SMC phenotype in MFS; (b) SMCs receive a complex combination of TGF‐β‐induced signals ultimately producing a mixed synthetic‐contractile phenotype that likely disrupts aortic homeostasis; and (c) ERK‐dependent Notch3 overexpression may be an intrinsic protective response against aneurysm growth. This evidence concerns the gene NOTCH3 and aneurysm.