Evidence of Aortopathy in Mice with Haploinsufficiency ofNotch1inNos3-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 inNOTCH1have been linked to bicuspid aortic valve (BAV) and aortopathy in humans. The aim of this study was to determine if haploinsufficiency ofNotch1contributes to aortopathy usingNotch1+/-; Nos3-/-mice. Echocardiographic analysis ofNotch1+/-; Nos3-/-mice reveals effacement of the sinotubular junction and a trend toward dilation of the aortic sinus. Furthermore, examination of the proximal aorta ofNotch1+/-; 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 inNotch1heterozygote mice and inNos3-null mice. Our findings implicate a novel role for Notch1 in aortopathy of the proximal aorta.
The Center for Cardiovascular and Pulmonary Research and Heart Center, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA ; Department of Pediatrics, The Ohio State University, 700 Children's Drive, Columbus, OH 43205, USA.
Sara N
SN
Koenig
The Center for Cardiovascular and Pulmonary Research and Heart Center, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA.
Kevin M
KM
Bosse
The Center for Cardiovascular and Pulmonary Research and Heart Center, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA ; Department of Pediatrics, The Ohio State University, 700 Children's Drive, Columbus, OH 43205, USA.
Holly A
HA
Nadorlik
The Center for Cardiovascular and Pulmonary Research and Heart Center, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA ; Department of Pediatrics, The Ohio State University, 700 Children's Drive, Columbus, OH 43205, USA.
Brenda
B
Lilly
The Center for Cardiovascular and Pulmonary Research and Heart Center, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA ; Department of Pediatrics, The Ohio State University, 700 Children's Drive, Columbus, OH 43205, USA ; Department of Molecular Genetics, The Ohio State University, 484 West 12th Avenue, Columbus, OH 43210, USA.
Vidu
V
Garg
Notch; ascending aortic dilation; endothelial nitric oxide; sinotubular junction effacement; smooth muscle cell lineage