Age and Sex Dependency of Thoracic Aortopathy in a Mouse Model of Marfan Syndrome

Thoracic aortic aneurysm is one of the manifestations of Marfan syndrome (MFS) that is known to affect men more severely than women. However, the incidence of MFS is similar between men and women. The aim of this study is to show that during pathological aortic dilation, sex-dependent severity of thoracic aortopathy in a mouse model of Marfan syndrome translates into sex-dependent alterations in cells and matrix of the ascending aorta, consequently affecting aortic biomechanics. Fibrillin1 C1041G/+ were used as a mouse model of MFS. Ultrasound measurements from 3-12 months showed increased aortic diameter in Marfan aorta with larger percent increase in diameter for males compared to females. Immunohistochemistry showed decreased contractile smooth muscle cells in Marfan aortic wall compared to healthy aorta, which was accompanied by decreased contractility measured by wire myography. Elastin autofluorescence, second harmonic generation microscopy of collagen fibers and passive biomechanical assessments using myography showed more severe damage to elastin fibers, increased medial fibrosis, and increased stiffness of the aortic wall in MFS males but not females. Male and female heterozygotes showed increased expression of Sca-1-positive adventitial progenitor cells vs. controls at young ages. In agreement with clinical data, Marfan mice demonstrate sex-dependent severity of thoracic aortopathy. It was also shown that aging exacerbates the disease state especially for males. Our findings suggest that female mice are protected from progression of aortic dilation at early ages, leading to a lag in aneurysm growth.

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Effect of the Antioxidant Lipoic Acid in Aortic Phenotype in a Marfan Syndrome Mouse Model

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/3967213 ◽

2018 ◽

Vol 2018 ◽

pp. 1-16 ◽

Cited By ~ 1

Author(s):

Maria C. Guido ◽

Victor Debbas ◽

Vera M. Salemi ◽

Elaine R. Tavares ◽

Thayna Meirelles ◽

...

Keyword(s):

Mouse Model ◽

Marfan Syndrome ◽

Lipoic Acid ◽

Elastic Fiber ◽

Aortic Aneurysms ◽

Ros Generation ◽

Ros Production ◽

Aortic Dilation ◽

Advanced Stages ◽

Aortic Remodeling

Marfan syndrome (MFS) cardiovascular manifestations such as aortic aneurysms and cardiomyopathy carry substantial morbidity/mortality. We investigated the effects of lipoic acid, an antioxidant, on ROS production and aortic remodeling in a MFS mgΔloxPneo mouse model. MFS and WT (wild-type) 1-month-old mice were allocated to 3 groups: untreated, treated with losartan, and treated with lipoic acid. At 6 months old, echocardiography, ROS production, and morphological analysis of aortas were performed. Aortic ROS generation in 6-month-old MFS animals was higher at advanced stages of disease in MFS. An unprecedented finding in MFS mice analyzed by OCT was the occurrence of focal inhomogeneous regions in the aortic arch, either collagen-rich extremely thickened or collagen-poor hypotrophic regions. MFS animals treated with lipoic acid showed markedly reduced ROS production and lower ERK1/2 phosphorylation; meanwhile, aortic dilation and elastic fiber breakdown were unaltered. Of note, lipoic acid treatment associated with the absence of focal inhomogeneous regions in MFS animals. Losartan reduced aortic dilation and elastic fiber breakdown despite no change in ROS generation. In conclusion, oxidant generation by itself seems neutral with respect to aneurysm progression in MFS; however, lipoic acid-mediated reduction of inhomogeneous regions may potentially associate with less anisotropy and reduced chance of dissection/rupture.

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Oxytocin antagonism prevents pregnancy-associated aortic dissection in a mouse model of Marfan syndrome

Science Translational Medicine ◽

10.1126/scitranslmed.aat4822 ◽

2019 ◽

Vol 11 (490) ◽

pp. eaat4822 ◽

Cited By ~ 10

Author(s):

Jennifer Pardo Habashi ◽

Elena Gallo MacFarlane ◽

Rustam Bagirzadeh ◽

Caitlin Bowen ◽

Nicholas Huso ◽

...

Keyword(s):

Aortic Dissection ◽

Mouse Model ◽

Marfan Syndrome ◽

Uterine Contraction ◽

Aortic Wall ◽

Erk Activation ◽

Extracellular Signal Regulated Kinase ◽

Erk Phosphorylation ◽

Extracellular Signal ◽

Erk Kinase

Women with Marfan syndrome (MFS) are at high risk for pregnancy-associated aortic dissection. Pathogenic models that singularly invoke hemodynamic stress are difficult to reconcile with predominant postnatal occurrence of aortic tear, often occurring weeks to months after delivery. In consideration of events that peak at term, are sustained after delivery, and might synergize with previously defined signaling pathways implicated in aneurysm progression, we examined the hormone oxytocin, which initiates uterine contraction and milk letdown for the duration of lactation through phosphorylation of extracellular signal–regulated kinase (ERK). In a mouse model of MFS that shows highly penetrant postnatal aortic dissection, risk was strongly attenuated by preventing lactation or use of an oxytocin receptor antagonist. Survival correlated inversely with the extent of ERK activation in the aortic wall, and strong protection was observed upon attenuation of ERK phosphorylation using an inhibitor of ERK kinase (MEK) or the U.S. Food and Drug Administration–approved medication hydralazine, offering potential therapeutic strategies for pregnancy-associated vascular catastrophe in the setting of MFS.

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IL‐6 Regulates Extracellular Matrix Remodeling Associated With Aortic Dilation in a Fibrillin‐1 Hypomorphic mgR/mgR Mouse Model of Severe Marfan Syndrome

Journal of the American Heart Association ◽

10.1161/jaha.113.000476 ◽

2014 ◽

Vol 3 (1) ◽

Cited By ~ 42

Author(s):

Xiaoxi Ju ◽

Talha Ijaz ◽

Hong Sun ◽

Wanda LeJeune ◽

Gracie Vargas ◽

...

Keyword(s):

Extracellular Matrix ◽

Mouse Model ◽

Marfan Syndrome ◽

Extracellular Matrix Remodeling ◽

Matrix Remodeling ◽

Aortic Dilation ◽

Fibrillin 1

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Analysis of second-harmonic-generation microscopy in a mouse model of ovarian carcinoma

Journal of Biomedical Optics ◽

10.1117/1.jbo.17.7.076002 ◽

2012 ◽

Vol 17 (7) ◽

pp. 0760021 ◽

Cited By ~ 17

Author(s):

Jennifer M. Watson ◽

Photini F. Rice ◽

Samuel L. Marion ◽

Molly A. Brewer ◽

John R. Davis ◽

...

Keyword(s):

Mouse Model ◽

Second Harmonic Generation ◽

Ovarian Carcinoma ◽

Harmonic Generation ◽

Second Harmonic ◽

Second Harmonic Generation Microscopy

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

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/hq0701.092136 ◽

2001 ◽

Vol 21 (7) ◽

pp. 1184-1189 ◽

Cited By ~ 80

Author(s):

Valérie Marque ◽

Pascal Kieffer ◽

Barbara Gayraud ◽

Isabelle Lartaud-Idjouadiene ◽

Francesco Ramirez ◽

...

Keyword(s):

Mouse Model ◽

Transgenic Mouse ◽

Marfan Syndrome ◽

Aortic Wall ◽

Transgenic Mouse Model

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Mild aerobic exercise blocks elastin fiber fragmentation and aortic dilatation in a mouse model of Marfan syndrome associated aortic aneurysm

Journal of Applied Physiology ◽

10.1152/japplphysiol.00132.2017 ◽

2017 ◽

Vol 123 (1) ◽

pp. 147-160 ◽

Cited By ~ 16

Author(s):

Christine Gibson ◽

Cory Nielsen ◽

Ramona Alex ◽

Kimbal Cooper ◽

Michael Farney ◽

...

Keyword(s):

Aortic Aneurysm ◽

Mouse Model ◽

Aerobic Exercise ◽

Marfan Syndrome ◽

Aortic Wall ◽

Clinical Care ◽

Structure And Function ◽

Strenuous Exercise ◽

Aortic Dilatation ◽

And Function

Regular low-impact physical activity is generally allowed in patients with Marfan syndrome, a connective tissue disorder caused by heterozygous mutations in the fibrillin-1 gene. However, being above average in height encourages young adults with this syndrome to engage in high-intensity contact sports, which unfortunately increases the risk for aortic aneurysm and rupture, the leading cause of death in Marfan syndrome. In this study, we investigated the effects of voluntary (cage-wheel) or forced (treadmill) aerobic exercise at different intensities on aortic function and structure in a mouse model of Marfan syndrome. Four-week-old Marfan and wild-type mice were subjected to voluntary and forced exercise regimens or sedentary lifestyle for 5 mo. Thoracic aortic tissue was isolated and subjected to structural and functional studies. Our data showed that exercise improved aortic wall structure and function in Marfan mice and that the beneficial effect was biphasic, with an optimum at low intensity exercise (55–65% V̇o2max) and tapering off at a higher intensity of exercise (85% V̇o2max). The mechanism underlying the reduced elastin fragmentation in Marfan mice involved reduction of the expression of matrix metalloproteinases 2 and 9 within the aortic wall. These findings present the first evidence of potential beneficial effects of mild exercise on the structural integrity of the aortic wall in Marfan syndrome associated aneurysm. Our finding that moderate, but not strenuous, exercise protects aortic structure and function in a mouse model of Marfan syndrome could have important implications for the medical care of young Marfan patients. NEW & NOTEWORTHY The present study provides conclusive scientific evidence that daily exercise can improve aortic health in a mouse model of Marfan syndrome associated aortic aneurysm, and it establishes the threshold for the exercise intensity beyond which exercise may not be as protective. These findings establish a platform for a new focus on promoting regular exercise in Marfan patients at an optimum intensity and create a paradigm shift in clinical care of Marfan patients suffering from aortic aneurysm complications.

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