The progression of aortic aneurysms involves complex changes in wall structure and results from the interplay of multiple cell types including endothelial cells, SMCs, macrophages and adventitial cells. It is important to realize that these pathogenic steps play out on different response backgrounds in the ascending thoracic aorta compared to the abdominal aorta. Much like genetic modifiers at work in different inbred strains of mice that can sometimes produce dramatically different phenotypic manifestations of the same mutation on different genetic backgrounds, the SMC lineage diversity intrinsic to different aortic segments may play important modifier roles in the origins and progression of aneurysms in thoracic versus abdominal aortic segments in the same individual. Future work will focus on identification of factors produced by endothelial cells exposed to chronic infusions of AngII that initiate response cascades in SMCs and macrophages leading to aneurysm formation. It will also bring into greater focus the ways that advances in understanding basic pathways of vascular development provide important insights into mechanisms of disease pathogenesis in the adult vascular system.