Experimental aortic aneurysm severity and growth depend on topical elastase concentration and lysyl oxidase inhibition

Berman, Alycia G.; Romary, Daniel J.; Kerr, Katherine E.; Gorazd, Natalyn E; Wigand, Morgan M; Patnaik, Sourav S.; Finol, Ender A.; Cox, Abigail; Goergen, Craig J.

doi:10.1038/s41598-021-04089-8

Cited by 23 publications

(11 citation statements)

References 55 publications

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“…39 Conversely, an elastase+BAPN model of abdominal aortic aneurysms reported greater dilatation in female than male mice, though with low numbers of females. 40 There is a need for further study of sex differences in aortopathy, particularly given the sexual dimorphism in aortic dissection in humans, wherein males are at greater risk than females 41 similar to our findings herein.…”

Section: Discussionsupporting

confidence: 77%

Effects of Age, Sex, and Extracellular Matrix Integrity on Aortic Dilatation and Rupture in a Mouse Model of Marfan Syndrome

Weiss

Rego

Cavinato

et al. 2023

ATVB

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BACKGROUND: Transmural failure of the aorta is responsible for substantial morbidity and mortality; it occurs when mechanical stress exceeds strength. The aortic root and ascending aorta are susceptible to dissection and rupture in Marfan syndrome, a connective tissue disorder characterized by a progressive reduction in elastic fiber integrity. Whereas competent elastic fibers endow the aorta with compliance and resilience, cross-linked collagen fibers confer stiffness and strength. We hypothesized that postnatal reductions in matrix cross-linking increase aortopathy when turnover rates are high. METHODS: We combined ex vivo biaxial mechanical testing with multimodality histological examinations to quantify expected age- and sex-dependent structural vulnerability of the ascending aorta in Fbn1 C1041G/+ Marfan versus wild-type mice without and with 4-week exposures to β-aminopropionitrile, an inhibitor of lysyl oxidase–mediated cross-linking of newly synthesized elastic and collagen fibers. RESULTS: We found a strong β-aminopropionitrile–associated sexual dimorphism in aortic dilatation in Marfan mice and aortic rupture in wild-type mice, with dilatation correlating with compromised elastic fiber integrity and rupture correlating with compromised collagen fibril organization. A lower incidence of rupture of β-aminopropionitrile–exposed Marfan aortas associated with increased lysyl oxidase, suggesting a compensatory remodeling of collagen that slows disease progression in the otherwise compromised Fbn1 C1041G/+ aorta. CONCLUSIONS: Collagen fiber structure and function in the Marfan aorta are augmented, in part, by increased lysyl oxidase in female and especially male mice, which improves structural integrity, particularly via fibrils in the adventitia. Preserving or promoting collagen cross-linking may represent a therapeutic target for an otherwise vulnerable aorta.

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Section: Discussionsupporting

confidence: 77%

Effects of Age, Sex, and Extracellular Matrix Integrity on Aortic Dilatation and Rupture in a Mouse Model of Marfan Syndrome

Weiss

Rego

Cavinato

et al. 2023

ATVB

View full text Add to dashboard Cite

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“…Importantly, orchiectomy and ovariectomy studies in WT mice suggest that androgens reduce LOX in the male aortas, hence rendering them vulnerable mechanically 50 . Conversely, an elastase + BAPN model of abdominal aortic aneurysms reported greater dilatation in female than male mice, though with low numbers of female mice 51 . There is clearly a need for a detailed study of the remarkable sex differences observed herein and in related models.…”

Section: Discussionmentioning

confidence: 91%

Compensatory aortic remodeling in Marfan syndrome protects against sexually dimorphic rupture during a BAPN challenge

Weiss

Rego

Cavinato

et al. 2022

Preprint

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Transmural rupture of the aorta is responsible for significant morbidity and mortality; it occurs when wall stress exceeds local wall strength. Amongst other conditions, the aortic root and ascending aorta become vulnerable to dissection and rupture in Marfan syndrome, a connective tissue disorder that results in a progressive fragmentation and degradation of the elastic fibers of the aortic wall. Whereas competent elastic fibers are critical for aortic functionality, cross-linked collagen fibers endow the aorta with its stiffness and strength. In this paper, we contrast progressive degeneration of the ascending aorta in male and female Marfan and wild-type mice, with and without chronic exposure to a potent inhibitor of lysyl oxidase (β-aminopropionitrile, or BAPN), to examine effects of extracellular matrix cross-linking in aortic dilatation and rupture. We found a strong sexual dimorphism in aortic dilatation in Marfan mice and aortic rupture in wild-type mice, but also a compensatory remodeling of the aorta that protected the Marfan aorta against lethal rupture despite a strong BAPN challenge. This compensation appears to be mediated via increased lysyl oxidase in the female and especially male Marfan aorta, resulting in improved collagen fiber stability and integrity, particularly of fibril bundles in the adventitia.

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“…In contrast, a previous study using BAPN administration with topical elastase application reported that female mice have accelerated aneurysm growth, enhanced dilatation, and higher mortality compared to their male counterparts. 46 Multiple factors may contribute to the differences between the previous and our studies, warranting further investigation to elucidate the underlying mediating mechanisms.…”

Section: Discussionmentioning

confidence: 71%

β-aminopropionitrile Induces Distinct Pathologies in the Ascending and Descending Thoracic Aortic Regions of Mice

Franklin,

Sawada,

Ito

et al. 2023

Preprint

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This study characterized β-aminopropionitrile (BAPN)-induced aortopathies in young mice. The effects of BAPN were first determined with regard to BAPN dose and mouse strain, age, and sex. BAPN-induced aortic rupture predominantly occurred or originated in the descending thoracic aorta. For mice surviving 12 weeks of BAPN administration, profound dilatation was consistently observed in the ascending region, while there were more heterogeneous changes in the descending thoracic region. Pathological features were distinct between the ascending and descending thoracic regions. Aortic pathology in the ascending region was characterized by luminal dilatation and elastic fiber disruption throughout the media. The descending thoracic region frequently had dissections with false lumen formation, macrophage infiltration, collagen deposition, and remodeling of the wall surrounding the false lumen. Cells surrounding the false lumen were predominantly positive for α-smooth muscle actin. To investigate the molecular basis of the regional heterogeneity, ascending and descending thoracic aortas were harvested after one week of BAPN administration prior to the appearance of overt pathology. BAPN compromised contractile properties in both regions equivalently, and RNA sequencing did not show obvious differences between the two aortic regions in smooth muscle cell markers, cell proliferation markers, and extracellular components. In conclusion, BAPN-induced pathologies show distinct, heterogeneous features within and between ascending and descending aortic regions in young mice.

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Experimental aortic aneurysm severity and growth depend on topical elastase concentration and lysyl oxidase inhibition

Cited by 23 publications

References 55 publications

Effects of Age, Sex, and Extracellular Matrix Integrity on Aortic Dilatation and Rupture in a Mouse Model of Marfan Syndrome

Effects of Age, Sex, and Extracellular Matrix Integrity on Aortic Dilatation and Rupture in a Mouse Model of Marfan Syndrome

Compensatory aortic remodeling in Marfan syndrome protects against sexually dimorphic rupture during a BAPN challenge

β-aminopropionitrile Induces Distinct Pathologies in the Ascending and Descending Thoracic Aortic Regions of Mice

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