Evidence of Aortopathy in Mice with Haploinsufficiency of Notch1 in Nos3-Null Background
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 determ...
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doaj-02c504b9cb0e4911881404bfaef3261c2020-11-24T23:20:10ZengMDPI AGJournal of Cardiovascular Development and Disease2308-34252015-03-0121173010.3390/jcdd2010017jcdd2010017Evidence of Aortopathy in Mice with Haploinsufficiency of Notch1 in Nos3-Null BackgroundSara N. Koenig0Kevin M. Bosse1Holly A. Nadorlik2Brenda Lilly3Vidu Garg4The Center for Cardiovascular and Pulmonary Research and Heart Center, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USAThe Center for Cardiovascular and Pulmonary Research and Heart Center, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USAThe Center for Cardiovascular and Pulmonary Research and Heart Center, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USAThe Center for Cardiovascular and Pulmonary Research and Heart Center, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USAThe Center for Cardiovascular and Pulmonary Research and Heart Center, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USAThoracic 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.http://www.mdpi.com/2308-3425/2/1/17ascending aortic dilationNotchendothelial nitric oxidesinotubular junction effacementsmooth muscle cell lineage |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sara N. Koenig Kevin M. Bosse Holly A. Nadorlik Brenda Lilly Vidu Garg |
spellingShingle |
Sara N. Koenig Kevin M. Bosse Holly A. Nadorlik Brenda Lilly Vidu Garg Evidence of Aortopathy in Mice with Haploinsufficiency of Notch1 in Nos3-Null Background Journal of Cardiovascular Development and Disease ascending aortic dilation Notch endothelial nitric oxide sinotubular junction effacement smooth muscle cell lineage |
author_facet |
Sara N. Koenig Kevin M. Bosse Holly A. Nadorlik Brenda Lilly Vidu Garg |
author_sort |
Sara N. Koenig |
title |
Evidence of Aortopathy in Mice with Haploinsufficiency of Notch1 in Nos3-Null Background |
title_short |
Evidence of Aortopathy in Mice with Haploinsufficiency of Notch1 in Nos3-Null Background |
title_full |
Evidence of Aortopathy in Mice with Haploinsufficiency of Notch1 in Nos3-Null Background |
title_fullStr |
Evidence of Aortopathy in Mice with Haploinsufficiency of Notch1 in Nos3-Null Background |
title_full_unstemmed |
Evidence of Aortopathy in Mice with Haploinsufficiency of Notch1 in Nos3-Null Background |
title_sort |
evidence of aortopathy in mice with haploinsufficiency of notch1 in nos3-null background |
publisher |
MDPI AG |
series |
Journal of Cardiovascular Development and Disease |
issn |
2308-3425 |
publishDate |
2015-03-01 |
description |
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. |
topic |
ascending aortic dilation Notch endothelial nitric oxide sinotubular junction effacement smooth muscle cell lineage |
url |
http://www.mdpi.com/2308-3425/2/1/17 |
work_keys_str_mv |
AT sarankoenig evidenceofaortopathyinmicewithhaploinsufficiencyofnotch1innos3nullbackground AT kevinmbosse evidenceofaortopathyinmicewithhaploinsufficiencyofnotch1innos3nullbackground AT hollyanadorlik evidenceofaortopathyinmicewithhaploinsufficiencyofnotch1innos3nullbackground AT brendalilly evidenceofaortopathyinmicewithhaploinsufficiencyofnotch1innos3nullbackground AT vidugarg evidenceofaortopathyinmicewithhaploinsufficiencyofnotch1innos3nullbackground |
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