Abstract 1014: Molecular Dynamics In The Progression Of Aortic Dissection With Emphasis On De Novo Elastic Fiber Synthesis

Abstract

Background: Aortic dissection (AD) confined to the descending thoracic aorta is typically managed conservatively in the acute phase. However, these patients often require surgeries due to aortic dilatation in the chronic phase. Although preclinical studies have been conducted to investigate the mechanism of AD, most studies focused on the acute phase, especially the cause of AD. It remains unknown how molecular mechanisms alter following AD. Methods and Results: To determine the molecular alteration after AD, bulk RNA sequencing was performed using aortas from mice administered β-aminopropionitrile (BAPN) for 1, 4, or 12 weeks that represent pre, acute, and chronic phases of ADs, respectively. There were 6,755 differentially expressed genes (DEGs), and 2,667 and 1,173 DEGs were upregulated in the acute and chronic phases, respectively. Gene ontology analysis revealed that DEGs in the acute phase were related to inflammation, whereas DEGs in the chronic phase were associated with extracellular matrix. Those DEGs in the chronic phase included tropoelastin ( Eln ), the precursor of elastic fibers. In situ hybridization and immunostaining demonstrated that Eln mRNA and protein were distributed in the vascular wall of the false lumen. Of note, these molecules formed new elastic fibers, as evidenced by Verhoeff’s iron hematoxylin staining. The de novo fibers were thinner than native fibers; however, ultrasonography revealed that aortas with AD lesions had higher elasticity and distensibility compared to intact aortas. These data suggest that new elastic fibers protect against aortic rupture after AD. Next, a transcriptional factor prediction analysis was performed to identify a potential regulator of Eln transcription and found that Etv5 could be aligned in both the promoter and enhancer regions of Eln . Immunostaining showed that ETV5 was spatially coincident with Eln mRNA and de novo fibers. Conclusion: Genes related to the extracellular matrix are upregulated in response to AD in BAPN-administered mice. Elastic fibers are newly formed in the vascular wall of the false lumen in chronic AD accompanied by enhanced Etv5 .