Abstract
Cardiovascular manifestations are a major cause of mortality in Marfan syndrome (MFS). Animal models that mimic the syndrome and its clinical variability are instrumental for understanding the genesis and risk factors for cardiovascular disease in MFS. This study used morphological and ultrastructural analysis to the understanding of the development of cardiovascular phenotypes of the the mgΔloxPneo model for MFS. We studied 6-month-old female mice of the 129/Sv background, 6 wild type (WT) and 24 heterozygous animals from the mgΔloxPneo model. Descending thoracic aortic aneurysm and/or dissection (dTAAD) were identified in 75% of the MFS animals, defining two subgroups: MFS with (MFS+) and without (MFS-) dTAAD. Both subgroups showed increased fragmentation of elastic fibers, predominance of type I collagen surrounding the elastic fiber and fragmentation of interlaminar fibers when compared to WT. However, only MFS animals with spine tortuosity developed aortic aneurysm/dissection. The aorta of MFS+ animals were more tortuous compared to those of MFS- and WT mice, possibly causing perturbations of the luminal blood flow. This was evidenced by the detection of diminished aorta-blood flow in MFS+. Accordingly, only MFS+ animals presented a process of concentric cardiac hypertrophy and a significantly decreased ratio of left and right ventricle lumen area. We show that mgΔloxPneo model mimics the vascular disease observed in MFS patients. Furthermore, the study indicates role of thoracic spine deformity in the development of aorta diseases. We suggest that degradation of support structures of the aortic wall; deficiency in the sustenance of the thoracic vertebrae; and their compression over the adjacent aorta resulting in disturbed blood flow is a triad of factors involved in the genesis of dissection/aneurysm of thoracic aorta.
Highlights
Marfan syndrome (MFS) is an autosomal dominant disease of the connective tissue, with considerable clinical variation [1, 2, 3]
We show that mgΔloxPneo model mimics the vascular disease observed in MFS patients
The disease is caused by mutations in the FBN1 gene, which encodes fibrillin-1, the most abundant glycoprotein of the microfibrils of extracellular matrix (ECM) [4,5,6]
Summary
Marfan syndrome (MFS) is an autosomal dominant disease of the connective tissue, with considerable clinical variation [1, 2, 3]. Fibrillin-1 microfibrils are the scaffold for elastin deposition, forming the elastic fibers, a major component of the aortic wall [4,5].fibrillin-1 dysmorphism is considered to be the primary causal factor for the cardiovascular disease’s related morbidity and mortality in MFS. Mouse models of MFS have been instrumental in elucidating the complex molecular mechanisms underlying the disease. The mgΔloxPneo model for MFS has an in-frame deletion of exons 19–24 leading to the production of an internally truncated fibrillin-1 protein [7]. Heterozygotes in the Sv/129 isogenic background present MFS-phenotypes including kyphosis and elastic fiber disruption and thickening of the aortic media, with high phenotypic variability [7]. We identify other cardiovascular phenotypes and alterations in blood flux in the aorta in a subset of heterozygotes, and show a correlation between these phenotypes and thoracic spine tortuosity
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