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

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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.

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          Mutations in NOTCH1 cause aortic valve disease.

          Vidu Garg, Alecia N. Muth, Joshua F Ransom … (2005)
          Calcification of the aortic valve is the third leading cause of heart disease in adults. The incidence increases with age, and it is often associated with a bicuspid aortic valve present in 1-2% of the population. Despite the frequency, neither the mechanisms of valve calcification nor the developmental origin of a two, rather than three, leaflet aortic valve is known. Here, we show that mutations in the signalling and transcriptional regulator NOTCH1 cause a spectrum of developmental aortic valve anomalies and severe valve calcification in non-syndromic autosomal-dominant human pedigrees. Consistent with the valve calcification phenotype, Notch1 transcripts were most abundant in the developing aortic valve of mice, and Notch1 repressed the activity of Runx2, a central transcriptional regulator of osteoblast cell fate. The hairy-related family of transcriptional repressors (Hrt), which are activated by Notch1 signalling, physically interacted with Runx2 and repressed Runx2 transcriptional activity independent of histone deacetylase activity. These results suggest that NOTCH1 mutations cause an early developmental defect in the aortic valve and a later de-repression of calcium deposition that causes progressive aortic valve disease.
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            Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type.

            M. Pepin, U Schwarze, A Superti-Furga … (2000)
            Ehlers-Danlos syndrome type IV, the vascular type, results from mutations in the gene for type III procollagen (COL3A1). Affected patients are at risk for arterial, bowel, and uterine rupture, but the timing of these events, their frequency, and the course of the disease are not well documented. We reviewed the clinical and family histories of and medical and surgical complications in 220 index patients with biochemically confirmed Ehlers-Danlos syndrome type IV and 199 of their affected relatives. We identified the underlying COL3A1 mutation in 135 index patients. Complications were rare in childhood; 25 percent of the index patients had a first complication by the age of 20 years, and more than 80 percent had had at least one complication by the age of 40. The calculated median survival of the entire cohort was 48 years. Most deaths resulted from arterial rupture. Bowel rupture, which often involved the sigmoid colon, accounted for about a quarter of complications but rarely led to death. Complications of pregnancy led to death in 12 of the 81 women who became pregnant. The types of complications were not associated with specific mutations in COL3A1. Although most affected patients survive the first and second major complications, Ehlers-Danlos syndrome type IV results in premature death. The diagnosis should be considered in young people who come to medical attention because of uterine rupture during pregnancy or arterial or visceral rupture.
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              Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell.

              Shu Chien (2007)
              Vascular endothelial cells (ECs) play significant roles in regulating circulatory functions. Mechanical stimuli, including the stretch and shear stress resulting from circulatory pressure and flow, modulate EC functions by activating mechanosensors, signaling pathways, and gene and protein expressions. Mechanical forces with a clear direction (e.g., the pulsatile shear stress and the uniaxial circumferential stretch existing in the straight part of the arterial tree) cause only transient molecular signaling of pro-inflammatory and proliferative pathways, which become downregulated when such directed mechanical forces are sustained. In contrast, mechanical forces without a definitive direction (e.g., disturbed flow and relatively undirected stretch seen at branch points and other regions of complex geometry) cause sustained molecular signaling of pro-inflammatory and proliferative pathways. The EC responses to directed mechanical stimuli involve the remodeling of EC structure to minimize alterations in intracellular stress/strain and elicit adaptive changes in EC signaling in the face of sustained stimuli; these cellular events constitute a feedback control mechanism to maintain vascular homeostasis and are atheroprotective. Such a feedback mechanism does not operate effectively in regions of complex geometry, where the mechanical stimuli do not have clear directions, thus placing these areas at risk for atherogenesis. The mechanotransduction-induced EC adaptive processes in the straight part of the aorta represent a case of the "Wisdom of the Cell," as a part of the more general concept of the "Wisdom of the Body" promulgated by Cannon, to maintain cellular homeostasis in the face of external perturbations.
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                Author and article information

                Contributors
                Sara N. Koenig
                Kevin M. Bosse
                Holly A. Nadorlik
                Brenda Lilly
                Journal
                Journal ID (nlm-journal-id): 101651414
                Journal ID (pubmed-jr-id): 43558
                Journal ID (nlm-ta): J Cardiovasc Dev Dis
                Journal ID (iso-abbrev): J Cardiovasc Dev Dis
                Title: Journal of cardiovascular development and disease
                ISSN (Electronic): 2308-3425
                Publication date Nihms-submitted: 11 April 2015
                Publication date (Print): 2015
                Publication date PMC-release: 23 April 2015
                Volume: 2
                Issue: 1
                Pages: 17-30
                Affiliations
                [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 notes
                [* ]Author to whom correspondence should be addressed; Vidu.Garg@ 123456nationwidechildrens.org ; Tel.: +1-614-355-5740; Fax: +1-614-355-5725
                Article
                Manuscript ID: NIHMS679329
                DOI: 10.3390/jcdd2010017
                PMC ID: 4407710
                PubMed ID: 25914885
                SO-VID: c9957ed5-fb64-47af-a84c-fb22751bd6f1
                Copyright © © 2015 by the authors; license MDPI, Basel, Switzerland
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

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                Subject: Article

                Keywords: ascending aortic dilation,notch,endothelial nitric oxide,sinotubular junction effacement,smooth muscle cell lineage
                Data availability:
                Keywords: ascending aortic dilation, notch, endothelial nitric oxide, sinotubular junction effacement, smooth muscle cell lineage

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