In conjunction with AngII‐induced vascular inflammation mediated by the enhanced transmural infiltration of macrophages, these abnormalities predisposed S3KO mice to the development of highly penetrant and severe aortic aneurysms, recapitulating the pathologic phenotypes of human AOS.4–5 We further revealed that SMAD3 deficiency caused enhanced iNOS‐mediated NO production to predominantly activate elastolytic and collagenolytic MMP‐9 in the VSMCs, which in turn contributed to the initial structural defects observed in S3KO aortas prior to AngII treatment. This evidence concerns the gene SMAD3 and aortic aneurysm.