Abstract
Medial deterioration leading to thoracic aortic aneurysms arises from multiple causes, chief among them mutations to the gene that encodes fibrillin-1 and leads to Marfan syndrome. Fibrillin-1 microfibrils associate with elastin to form elastic fibers, which are essential structural, functional, and instructional components of the normal aortic wall. Compromised elastic fibers adversely impact overall structural integrity and alter smooth muscle cell phenotype. Despite significant progress in characterizing clinical, histopathological, and mechanical aspects of fibrillin-1 related aortopathies, a direct correlation between the progression of microstructural defects and the associated mechanical properties that dictate aortic functionality remains wanting. In this paper, age-matched wild-type, Fbn1C1041G/+, and Fbn1mgR/mgR mouse models were selected to represent three stages of increasing severity of the Marfan aortic phenotype. Ex vivo multiphoton imaging and biaxial mechanical testing of the ascending and descending thoracic aorta under physiological loading conditions demonstrated that elastic fiber defects, collagen fiber remodeling, and cell reorganization increase with increasing dilatation. Three-dimensional microstructural characterization further revealed radial patterns of medial degeneration that become more uniform with increasing dilatation while correlating strongly with increased circumferential material stiffness and decreased elastic energy storage, both of which comprise aortic functionality.
Highlights
Fibrillin-1 is an elastin-associated glycoprotein that plays important structural and instructional roles within the aortic wall [1], among other tissues
Fibrillin-1 appears to contribute significantly to the long-term stability of elastic fibers [2], which have a half-life on the order of decades [3], and to endow the aortic wall with much of its resilience [4]; it regulates the bioavailability of transforming growth factor-beta (TGFβ) by sequestering latent TGFβ binding proteins within the extracellular matrix [5]
Faury and colleagues reported, using a mouse model that expresses about 60% of normal fibrillin-1 (Fbn1mg /+), that compromised fibrillin-1 leads to a progressive phenotype characterized by disrupted elastic lamellae, increased inter-lamellar distances, dispersed collagen fibers, and an overall aortic dilatation and stiffening [9]
Summary
Fibrillin-1 is an elastin-associated glycoprotein that plays important structural and instructional roles within the aortic wall [1], among other tissues. Marfan Aortic Microstructure and Mechanics contributes to mechano-sensing and mechano-regulation of the extracellular matrix [7]. Multiple mouse models of fibrillin-1 deficiency have been used to study roles of this key glycoprotein on aortic structure, function, and disease progression. Ramirez and colleagues compared geometric, microstructural, and mechanical metrics in mice haploinsufficient for either elastin (Eln+/−) or fibrillin-1 (Fbn1+/−) and found both differential and complementary roles of these two key components of elastic fibers [8]. Faury and colleagues reported, using a mouse model that expresses about 60% of normal fibrillin-1 (Fbn1mg /+), that compromised fibrillin-1 leads to a progressive phenotype characterized by disrupted elastic lamellae, increased inter-lamellar distances, dispersed collagen fibers, and an overall aortic dilatation and stiffening [9]. In neither case was there a direct correlation between the microstructural defects and detailed metrics of the mechanical properties
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
