Abstract Aortopathies, including aneurysms, dissection, and rupture, represent a key challenge in HLBS research. In the past twenty years of our continuously funded research on aortopathies, we have contributed to many mechanistic insights into the aortopathy research including a new concept: There are regional characteristics of the aorta in regard to diverse embryonic origins and functions of cells. The overall hypothesis of this R35 program is that heterogeneity of cellular origins imparts functional variances along the length of the aorta, including diversity of extracellular matrix stability, which in turn contributes to regional specificity of aortopathies. Regional specificity of aortopathies is present in many mouse models that we have validated and characterized. Our initial single cell transcriptomic and proteomic data have also implicated new potential contributors to heterogeneity of the normal aortic biology and aortopathies. Three major themes are proposed in this program: (1) What are the structural and molecular mechanisms that contribute to biological and pathophysiological heterogeneity along the length of the aorta? (2) Are cellular and extracellular heterogeneity a basis for regional specificity of aortopathies? (3) How do signaling pathways, extracellular matrix, and crosstalk between resident aortic cells coordinate to promote the heterogeneity of aortopathies? We have robust tools including a spectrum of reagents, multiple classic and new mouse models, ultrasonography, MRI, intravital microscopy, proteomics, and single cell RNA sequencing techniques. In addition to aortopathy research, the PI has more than 30-year expertise in the fields of lipoprotein metabolism, inflammation, and atherosclerosis research. Aortopathies are not a sole aortic disease, but is associated with a wide range of diseases or syndromes that may affect skin, lung, kidney, brain, bone, and other organs. The proposed research program will benefit from the flexibility to pursue potential contributions of other tissues and organs to aortopathies, and vice versa the influences of aortopathies on other tissues and organs. This R35 mechanism will also benefit the PI’s strength in basic research, enhance his interaction with the translational research in the clinical arena, and train the next generation of scientists.