Sexually Dimorphic Mechanisms in Human Thoracic Aortic Aneurysm.

PROJECT SUMMARY Thoracic aortic aneurysm and dissection (TAAD) are among the major causes of morbidity and mortality in the United States. Thoracic aortic aneurysms (TAAs) show sex differences in growth rates and outcomes for unknown reasons. Despite the well-established role of genetic predisposition in TAA formation, the majority of TAA patients do not have a family history of the disease or syndromic features, with disease presentations at older ages. Causes of sporadic TAA are insufficiently understood. Current TAA treatment is limited to surgical intervention due to inadequate understanding of the disease pathogenesis specific to humans. Ambiguities still exist regarding the spatial remodeling in human TAA tissue, leaving the disease-causing and protective changes unexplored. Therefore, molecular and functional characterization of the cells constituting human TAA tissue is vital in understanding the mechanistic underpinnings of sex differences in TAA formation and outcomes. Using high-resolution spatial profiling, we discovered spatially-distinct CARTPT (CART prepropeptide) expressing cells predominantly in male sporadic ascending TAAs. Our hypothesis is that sexually-dimorphic CART signaling mediates aortic wall remodeling and medial calcification in male TAAs. Medial calcification reduces vessel compliance and increases arterial stiffness, but whether it is a friend or a foe (or both) in TAA pathogenesis remains to be determined. The aims of proposed project are the following: (1) Define the molecular triggers and consequences of CART signaling in aortic smooth muscle cells in vitro, and (2) Determine the role of sexually dimorphic signaling mechanisms in TAA pathogenesis in vivo. To investigate the proposed aims, we will utilize a toolset tailored for basic human research including human derived smooth muscle cells, bioengineered human vascular grafts and high-content single molecule spatial transcriptomics profiling of surgically resected TAA samples as reference points. Achievement of the proposed studies will resolve the regulation and the functional relevance of sexually dimorphic cells and signaling pathways in human TAAs with an emphasis on CART signaling, determine how these sex differences influence TAA outcomes and provide high resolution spatial maps of male and female TAAs.