title: Myh11(R247C/R247C) mutations increase thoracic aorta vulnerability to intramural damage despite a general biomechanical adaptivity.
abstract: Genetic studies in patients reveal that mutations to genes that encode contractile proteins in medial smooth muscle cells can cause thoracic aortic aneurysms and dissections. Mouse models of such mutations, including Acta2(-/-) and Myh11(R247C/R247C), surprisingly do not present with any severe vascular phenotype under normal conditions. This observation raises the question whether these mutations nevertheless render the thoracic aorta increasingly vulnerable to aneurysms or dissections in the presence of additional, epigenetic, factors such as hypertension, a known risk factor for thoracic aortic disease. Accordingly, we compared the structure and biaxial mechanical properties of the ascending and descending thoracic aorta from male wild-type and Myh11(R247C/R247C) mice under normotension and induced hypertension. On average, the mutant aortas exhibited near normal biomechanics under normotensive hemodynamics and near normal adaptations to hypertensive hemodynamics, yet the latter led to intramural delaminations or premature deaths in over 20% of these mice. Moreover, the delaminated vessels exhibited localized pools of mucoid material, similar to the common histopathologic characteristic observed in aortas from humans affected by thoracic aortic aneurysms and dissections. The present findings suggest, therefore, that mutations to smooth muscle cell contractile proteins may place the thoracic aorta at increased risk to epigenetic factors and that there is a need to focus on focal, not global, changes in aortic structure and properties, including the pooling of glycosaminoglycans/proteoglycans that may lead to thoracic aortic dissection.
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT, 06511, USA. Electronic address: chiara.bellini@yale.edu.
authors.forename: Chiara
authors.initials: C
authors.lastname: Bellini
authors.affiliation: Department of Internal Medicine, University of Texas Health Science Center, Houston, TX, USA.
authors.forename: Shanzhi
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, University of Texas Health Science Center, Houston, TX, USA.
authors.forename: Dianna M
authors.initials: DM
authors.lastname: Milewicz
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT, 06511, USA.
authors.forename: Jay D
authors.initials: JD
authors.lastname: Humphrey
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D001013:Aorta, Thoracic / Q000473:pathology / Q000503:physiopathology*; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics*; D004195:Disease Models, Animal; D006439:Hemodynamics; D006801:Humans; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D032389:Myocytes, Smooth Muscle; D018995:Myosin Heavy Chains / Q000235:genetics*; D010641:Phenotype
chemical_list: C573943:myosin 11, mouse; D018995:Myosin Heavy Chains
keywords: Actomyosin functionality; Familial thoracic aortic aneurysms and dissections; Smooth muscle myosin heavy chain; Wall stress and stiffness