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Aortic wall mechanics and composition in a transgenic mouse model of Marfan syndrome
V Marque1, P Kieffer, B Gayraud
1Laboratoire de Pharmacologie Cardiovasculaire, Faculté de Pharmacie, Université Henri Poincaré-Nancy, Nancy, France.
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 (0.80+/-0.06 vs 0.63+/-0.03 mm in wild type, P<0.05) 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 432+/-31 vs wild type 492+/-42 microg/mg wet weight, P>0.05). Elastic fibers showed severe fragmentation: the percentage of the media occupied by elastic fibers was 18+/-3% in mgR/mgR mice vs 30+/-1% in wild-type mice, with the number of elastic segments being 1.9+/-0.2 vs 1.4+/-0.1x10(-6)/mm(2) in the wild type (both P<0.05). 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.
Insights
Marfan syndrome causes aortic aneurysm due to fibrillin gene (FBN1) mutations. This study in mgR/mgR mice shows FBN1 underexpression leads to elastic fiber fragmentation, not impaired elastogenesis, causing aortic dilatation.
Area of Science:
- Cardiovascular Biology
- Genetics
- Connective Tissue Disorders
Background:
- Marfan syndrome, caused by fibrillin gene (FBN1) mutations, leads to thoracic aortic aneurysms and dissection.
- The exact mechanisms driving aneurysm formation in Marfan syndrome remain unclear.
- Distinguishing between early elastic fiber formation defects and later disruption is crucial.
Purpose of the Study:
- To investigate the sequence of events in aortic aneurysm formation in a mouse model of Marfan syndrome.
- To differentiate between a defect in early elastic fiber formation (elastogenesis) and elastic fiber disruption.
Main Methods:
- Utilized the mgR/mgR mouse model with hypomorphic FBN1 mutation, leading to FBN1 underexpression.
- Assessed early elastogenesis via desmosine plus isodesmosine content.
- Analyzed elastic fiber disruption using histomorphometry and measured aortic wall stiffness via pulse wave velocity.
Main Results:
- mgR/mgR mice exhibited severe elastic fiber fragmentation (18% vs 30% in wild-type) and aortic dilatation.
- No significant difference in desmosine content was observed, indicating normal early elastogenesis.
- Aortic wall stiffening occurred, but wall stress was not significantly modified due to compensatory increases in medial cross-sectional area.
Conclusions:
- FBN1 underexpression in mice results in significant elastic network fragmentation without affecting cross-linking.
- This fragmentation, not a defect in early elastogenesis, is a key factor in aortic dilatation in Marfan syndrome.
- Findings highlight the critical role of elastic fiber integrity in maintaining aortic structure and preventing aneurysm.