Aortic Wall Mechanics and Composition in a Transgenic Mouse Model of Marfan Syndrome

Abstract

Abstract-In Marfan syndrome, mutations of the fibrillin gene (FBN1) lead to aneurysm of the thoracic aorta, making the aortic wall more susceptible to dissection, but the precise sequence of events underlying aneurysm formation is unknown. We used a rodent model of Marfan syndrome, the mgR/mgR mouse (with mgR: hypomorphic FBN1 mutation), which underexpresses FBN1, to distinguish between a defect in the early formation of elastic fibers and the later disruption of elastic fibers. The content of desmosine plus isodesmosine was used as an index of early elastogenesis; disruption of elastic fibers was analyzed by histomorphometry. Because disruption of the medial elastic fibers may produce aortic stiffening, so amplifying the aneurysmal process, we measured thoracoabdominal pulse wave velocity as an indicator of aortic wall stiffness. Both mgR/mgR and wild-type (C57BL/6J-129SV) strains were normotensive, and wall stress was not significantly modified because the increase in internal diameter (0.80Ϯ0.06 vs 0.63Ϯ0.03 mm in wild type, PϽ0.05) was accompanied by increased medial cross-sectional area. The aortic wall stiffened (4-fold increase in the elastic modulus-to-wall stress ratio). Desmosine content was not modified (mgR/mgR 432Ϯ31 vs wild type 492Ϯ42 g/mg wet weight, PϾ0.05). Elastic fibers showed severe fragmentation: the percentage of the media occupied by elastic fibers was 18Ϯ3% in mgR/mgR mice vs 30Ϯ1% in wild-type mice, with the number of elastic segments being 1.9Ϯ0.2 vs 1.4Ϯ0.1ϫ10 Ϫ6/mm 2 in the wild type (both PϽ0.05). In conclusion, underexpression of FBN1 in mice leads to severe elastic network fragmentation but no change in cross-linking, together with aortic dilatation. This result suggests that fragmentation of the medial elastic network and not a defect in early elastogenesis is 1 of the determinants of aortic dilatation in Marfan syndrome. Key Words: fibrillin-1 Ⅲ elastic modulus Ⅲ aneurysm Ⅲ desmosines Ⅲ elastic fibers M arfan syndrome is a dominantly inherited disorder characterized by cardiovascular, skeletal, and ocular abnormalities. 1 The cardiovascular manifestations include aortic root dilatation and dissection that result in rupture of the vessel wall and premature death. Marfan syndrome has been associated with mutations of the gene coding for fibrillin-1 (FBN1), the major constituent of extracellular microfibrils. 2 However, the link between FBN1 deficiency and the development of aneurysm is not yet clearly established.Early ideas were based on the regulatory role played by microfibrils in the organized deposition of tropoelastin molecules during elastogenesis. 3 It was suggested that FBN1 mutations prevented normal cross-linking (formation of desmosine cross-bridges), leading to disorganized microfibrillar assembly, and that this weakened the mechanical strength of the media. This hypothesis was recently challenged by homologous gene-targeting experiments in the mouse, 4 which indicated that FBN1 microfibrils were predominantly engaged in global tissue homeostasis rather than in elasti...

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