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Structure-Function-Molecular Relationships Of The Extracellular Matrix Of Aortic Valves In Mouse Models Of Human Disease
Kaitlyn Thatcher1, Carol Mattern1, Jessica Fulton2, Felix Liu3, Michael McDermott4, Cristopher Breuer3, Brian Hoffmann5, Joy Lincoln1.
1Medical College of Wisconsin, Wauwatosa, WI, USA, 2Center for Cardiovascular Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA, 3Center for Regenerative Medicine, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA, 4Center for Cardiovascular Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA, 5The Jackson Laboratory, Bar Harbor, ME, USA.

OBJECTIVE: The organization of extracellular matrix (ECM) components, including collagens, proteoglycans, and elastins, into the fibrosa, spongiosa, and ventricularis layers respectively, is essential for maintaining proper structure and function of heart valves. Mutations in ECM components cause connective tissue disorders, including Osteogenesis Imperfecta (OI), and debilitating heart valve dysfunction in these patients is common. Currently, treatment is limited to surgical valve repair or replacement, causing insuperable complications for many patients, emphasizing a critical need for developing alternative approaches. This study models connective tissue disorders in mice to investigate valve pathogenesis, with the goal of developing more effective, mechanistic-based therapies.
METHODS: Mice with a frameshift mutation in the pro-alpha2 chain of collagenI (col1a2) serve as a model of OI Murine (OIM). Gross changes in aortic valve (AoV) morphology and ECM composition and organization were analyzed histologically at 3, 6, and 12 months of age, in parallel with mass spectrometry of decellularized AoV isolates at 3 months, electron microscopy at 9 months, and echocardiography at 3, 6, and 12 months.
RESULTS: The OIM-/- AoV shows significant thickening and myxomatous features, such as increased proteoglycan deposition and disorganization of the ECM, beginning as subtle changes from 3 months of age that worsen over time. Ultrastructural electron microscopy of AoV cusps reveal a trend towards decreased area and diameter of collagen fiber cross sections in the OIM-/- by 9 months. However, we observe no functional defects until 12-14 months, when 60% of OIM-/- mice exhibit AoV regurgitation and/or left ventricle enlargement. Mass spectrometry confirmed decreased ColIa2 in OIM-/- mice, and identified significant changes in other ECM components suggestive of remodeling, including fibromodulin (decreased in OIM-/-), collagenVIa5 and matrix gla protein (increased in OIM-/-). CONCLUSIONS: Together these studies provide mechanistic insights into the temporal pathogenesis of valve dysfunction associated with human connective tissue disorders.


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