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Cross Talk between NOTCH Signaling and Biomechanics in Human Aortic Valve Disease Pathogenesis
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J. Cardiovasc. Dev. Dis. 2015, 2(1), 17-30; doi:10.3390/jcdd2010017

Evidence of Aortopathy in Mice with Haploinsufficiency of Notch1 in Nos3-Null Background

1
The Center for Cardiovascular and Pulmonary Research and Heart Center, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA
2
Department of Pediatrics, The Ohio State University, 700 Children's Drive, Columbus, OH 43205, USA
3
Department of Molecular Genetics, The Ohio State University, 484 West 12th Avenue, Columbus, OH 43210, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Christine B. Kern
Received: 24 October 2014 / Revised: 20 February 2015 / Accepted: 25 February 2015 / Published: 9 March 2015
(This article belongs to the Special Issue Semilunar Valve Development and Disease)
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Abstract

Thoracic aortic aneurysms (TAA) are a significant cause of morbidity and mortality in humans. While the exact etiology is unknown, genetic factors play an important role. Mutations in NOTCH1 have been linked to bicuspid aortic valve (BAV) and aortopathy in humans. The aim of this study was to determine if haploinsufficiency of Notch1 contributes to aortopathy using Notch1+/−; Nos3−/− mice. Echocardiographic analysis of Notch1+/−; Nos3−/− mice reveals effacement of the sinotubular junction and a trend toward dilation of the aortic sinus. Furthermore, examination of the proximal aorta of Notch1+/−; Nos3−/− mice reveals elastic fiber degradation, a trend toward increased matrix metalloproteinase 2 expression, and increased smooth muscle cell apoptosis, features characteristic of aneurysmal disease. Although at a lower penetrance, we also found features consistent with aortopathic changes in Notch1 heterozygote mice and in Nos3-null mice. Our findings implicate a novel role for Notch1 in aortopathy of the proximal aorta. View Full-Text
Keywords: ascending aortic dilation; Notch; endothelial nitric oxide; sinotubular junction effacement; smooth muscle cell lineage ascending aortic dilation; Notch; endothelial nitric oxide; sinotubular junction effacement; smooth muscle cell lineage
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Koenig, S.N.; Bosse, K.M.; Nadorlik, H.A.; Lilly, B.; Garg, V. Evidence of Aortopathy in Mice with Haploinsufficiency of Notch1 in Nos3-Null Background. J. Cardiovasc. Dev. Dis. 2015, 2, 17-30.

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