Abstract 16557: Hemodynamic Stress Activates a Comprehensive Adaptive Program in Murine Aortic Cells That Protects the Aortic Wall and Maintains Aortic Homeostasis

Abstract

Background: The aorta adapts to changes in its biomechanical environment and insufficient adaptation results in aortic failure. However, the molecular and cellular processes underlying this adaptive response are poorly understood. In this study, we performed single-cell transcriptomic and single-cell epigenomic analyses to investigate gene expression and epigenetic regulation responses in aortas subjected to hemodynamic stress. Methods and Results: Angiotensin II infusion in wild-type mice (C57BL/6J) increased ascending aorta wall thickness that was associated with smooth muscle cell (SMC) proliferation and extracellular matrix (ECM) production. ScRNA-seq revealed an adaptive response in several SMC clusters that was characterized by upregulation of genes in processes such as proliferation, cell junction organization, ECM production and organization, wound healing, as well as DNA repair and anti-oxidation. ScATAC-seq showed increased chromatin accessibility at the locus of these adaptive genes. Motif analysis of the accessible regions showed that several transcription factors and chromatin architecture proteins may be involved in regulating these adaptive response genes. Among these, Yap1 was significantly activated in response to the aortic challenge. YAP1-based ChIP-seq in aortic SMCs indicated that YAP1 and its transcription partners can directly bind to genes involved in the adaptive response to biomechanical stretch. Finally, SMC-specific knockout of Yap1 resulted in a compromised adaptive response and increased expression of genes involved in protein disassembly or degradation, and cell death in all SMC clusters, leading to contractile dysfunction, aortic aneurysm, dissection, and rupture. Conclusion: In mice, hemodynamic stress induces a comprehensive and coordinated adaptive response in SMCs that is critical for maintaining aortic homeostasis. YAP1 in SMCs play an important role in promoting this adaptive response in aortic wall.