Special Issue "Semilunar Valve Development and Disease"

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A special issue of Journal of Cardiovascular Development and Disease (ISSN 2308-3425).

Deadline for manuscript submissions: closed (1 September 2014)

Special Issue Editor

Guest Editor
Dr. Christine B. Kern (Website)

Department of Regenerative Medicine and Cell biology, University of South Carolina, 171 Ashley Ave., Charleston, SC 29425, USA

Special Issue Information

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Cardiovascular Development and Disease is an international peer-reviewed Open Access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. For the first couple of issues the Article Processing Charge (APC) will be waived for well-prepared manuscripts. English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.

Published Papers (6 papers)

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Research

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Open AccessArticle Evidence of Aortopathy in Mice with Haploinsufficiency of Notch1 in Nos3-Null Background
J. Cardiovasc. Dev. Dis. 2015, 2(1), 17-30; doi:10.3390/jcdd2010017
Received: 24 October 2014 / Revised: 20 February 2015 / Accepted: 25 February 2015 / Published: 9 March 2015
Cited by 3 | PDF Full-text (2540 KB) | HTML Full-text | XML Full-text | Supplementary Files
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Semilunar Valve Development and Disease)
Open AccessArticle Cross Talk between NOTCH Signaling and Biomechanics in Human Aortic Valve Disease Pathogenesis
J. Cardiovasc. Dev. Dis. 2014, 1(3), 237-256; doi:10.3390/jcdd1030237
Received: 1 October 2014 / Revised: 13 November 2014 / Accepted: 17 November 2014 / Published: 1 December 2014
Cited by 1 | PDF Full-text (849 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Aortic valve disease is a burgeoning public health problem associated with significant mortality. Loss of function mutations in NOTCH1 cause bicuspid aortic valve (BAV) and calcific aortic valve disease. Because calcific nodules manifest on the fibrosa side of the cusp in low [...] Read more.
Aortic valve disease is a burgeoning public health problem associated with significant mortality. Loss of function mutations in NOTCH1 cause bicuspid aortic valve (BAV) and calcific aortic valve disease. Because calcific nodules manifest on the fibrosa side of the cusp in low fluidic oscillatory shear stress (OSS), elucidating pathogenesis requires approaches that consider both molecular and mechanical factors. Therefore, we examined the relationship between NOTCH loss of function (LOF) and biomechanical indices in healthy and diseased human aortic valve interstitial cells (AVICs). An orbital shaker system was used to apply cyclic OSS, which mimics the cardiac cycle and hemodynamics experienced by AVICs in vivo. NOTCH LOF blocked OSS-induced cell alignment in human umbilical vein endothelial cells (HUVECs), whereas AVICs did not align when subjected to OSS under any conditions. In healthy AVICs, OSS resulted in decreased elastin (ELN) and α-SMA (ACTA2). NOTCH LOF was associated with similar changes, but in diseased AVICs, NOTCH LOF combined with OSS was associated with increased α-SMA expression. Interestingly, AVICs showed relatively higher expression of NOTCH2 compared to NOTCH1. Biomechanical interactions between endothelial and interstitial cells involve complex NOTCH signaling that contributes to matrix homeostasis in health and disorganization in disease. Full article
(This article belongs to the Special Issue Semilunar Valve Development and Disease)
Open AccessArticle Ectopic Noggin in a Population of Nfatc1 Lineage Endocardial Progenitors Induces Embryonic Lethality
J. Cardiovasc. Dev. Dis. 2014, 1(3), 214-236; doi:10.3390/jcdd1030214
Received: 3 October 2014 / Revised: 1 November 2014 / Accepted: 7 November 2014 / Published: 20 November 2014
Cited by 3 | PDF Full-text (3363 KB) | HTML Full-text | XML Full-text
Abstract
The initial heart is composed of a myocardial tube lined by endocardial cells. The TGFβ superfamily is known to play an important role, as BMPs from the myocardium signal to the overlying endocardium to create an environment for EMT. Subsequently, BMP and [...] Read more.
The initial heart is composed of a myocardial tube lined by endocardial cells. The TGFβ superfamily is known to play an important role, as BMPs from the myocardium signal to the overlying endocardium to create an environment for EMT. Subsequently, BMP and TGFβ signaling pathways synergize to form primitive valves and regulate myocardial growth. In this study, we investigated the requirement of BMP activity by transgenic over-expression of extracellular BMP antagonist Noggin. Using Nfatc1Cre to drive lineage-restricted Noggin within the endocardium, we show that ectopic Noggin arrests cardiac development in E10.5-11 embryos, resulting in small hearts which beat poorly and die by E12.5. This is coupled with hypoplastic endocardial cushions, reduced trabeculation and fewer mature contractile fibrils in mutant hearts. Moreover, Nfatc1Cre-mediated diphtheria toxin fragment-A expression in the endocardium resulted in genetic ablation and a more severe phenotype with lethality at E11 and abnormal linear hearts. Molecular analysis demonstrated that endocardial Noggin resulted in a specific alteration of TGFβ/BMP-mediated signal transduction, in that, both Endoglin and ALK1 were downregulated in mutant endocardium. Combined, these results demonstrate the cell-autonomous requirement of the endocardial lineage and function of unaltered BMP levels in facilitating endothelium-cardiomyocyte cross-talk and promoting endocardial cushion formation. Full article
(This article belongs to the Special Issue Semilunar Valve Development and Disease)
Open AccessArticle Sox9- and Scleraxis-Cre Lineage Fate Mapping in Aortic and Mitral Valve Structures
J. Cardiovasc. Dev. Dis. 2014, 1(2), 163-176; doi:10.3390/jcdd1020163
Received: 26 August 2014 / Revised: 16 September 2014 / Accepted: 17 September 2014 / Published: 23 September 2014
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Abstract
Heart valves are complex structures composed of a heterogeneous population of valve interstitial cells (VICs), an overlying endothelium and highly organized layers of extracellular matrix. Alterations in valve homeostasis are characteristic of dysfunction and disease, however the mechanisms that initiate and promote [...] Read more.
Heart valves are complex structures composed of a heterogeneous population of valve interstitial cells (VICs), an overlying endothelium and highly organized layers of extracellular matrix. Alterations in valve homeostasis are characteristic of dysfunction and disease, however the mechanisms that initiate and promote valve pathology are poorly understood. Advancements have been largely hindered by the limited availability of tools for gene targeting in heart valve structures during embryogenesis and after birth. We have previously shown that the transcription factors Sox9 and Scleraxis (Scx) are required for heart valve formation and in this study we describe the recombination patterns of Sox9- and Scx-Cre lines at differential time points in aortic and mitral valve structures. In ScxCre; ROSA26GFP mice, recombination is undetected in valve endothelial cells (VECs) and low in VICs during embryogenesis. However, recombination increases in VICs from post natal stages and by 4 weeks side-specific patterns are observed. Using the inducible Sox9CreERT2 system, we observe recombination in VECs and VICs in the embryo, and high levels are maintained through post natal and juvenile stages. These Cre-drivers provide the field with new tools for gene targeting in valve cell lineages during differential stages of embryonic and post natal maturation and maintenance. Full article
(This article belongs to the Special Issue Semilunar Valve Development and Disease)
Open AccessArticle Characterization of Dermal Fibroblasts as a Cell Source for Pediatric Tissue Engineered Heart Valves
J. Cardiovasc. Dev. Dis. 2014, 1(2), 146-162; doi:10.3390/jcdd1020146
Received: 17 June 2014 / Revised: 29 July 2014 / Accepted: 20 August 2014 / Published: 26 August 2014
Cited by 1 | PDF Full-text (2626 KB) | HTML Full-text | XML Full-text
Abstract
There is continued debate regarding the appropriate cell type to replace valvular interstitial cells (VICs) in tissue engineered heart valves (TEHVs), particularly for pediatric patients. In this work, neonatal human dermal fibroblasts (nhDFFs) were compared to human pediatric VICs (hpVICs), based on [...] Read more.
There is continued debate regarding the appropriate cell type to replace valvular interstitial cells (VICs) in tissue engineered heart valves (TEHVs), particularly for pediatric patients. In this work, neonatal human dermal fibroblasts (nhDFFs) were compared to human pediatric VICs (hpVICs), based on their phenotypic and gene expression characteristics when cultured on collagen type I, fibronectin, fibrin, and tissue culture polystyrene (TCP) substrates. Similar confluency was achieved over the culture period on collagen and fibronectin between both cell types, although nhDFFs tended to reach lower confluence on collagen than on any other substrate. Morphologically, hpVICs tended to spread and form multiple extensions, while nhDFFs remained homogenously spindle-shaped on all substrates. PCR results indicated that fibroblasts did not differ significantly from VICs in gene expression when cultured on fibrin, whereas on collagen type I and fibronectin they showed increased α-SMA, xylosyltransferase I, and collagen type I expression (p < 0.05). However, protein expression of these targets, analyzed by immunocytochemistry and Western blotting, was not significantly different between cell types. These results suggest that nhDFFs express similar matrix production and remodeling genes as hpVICs, and the choice of substrate for TEHV construction can affect the growth and expression profile of nhDFFs as compared to native hpVICs. Full article
(This article belongs to the Special Issue Semilunar Valve Development and Disease)
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Review

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Open AccessReview Myths and Realities Relating to Development of the Arterial Valves
J. Cardiovasc. Dev. Dis. 2014, 1(3), 177-200; doi:10.3390/jcdd1030177
Received: 29 August 2014 / Revised: 22 September 2014 / Accepted: 24 September 2014 / Published: 30 September 2014
Cited by 5 | PDF Full-text (10845 KB) | HTML Full-text | XML Full-text
Abstract
There is considerable confusion as to how best describe the components of the arterial valves. It is hardly surprising, therefore, that similar uncertainties apply to concepts for their development. In this review, we describe the anatomy of the arterial valves as seen [...] Read more.
There is considerable confusion as to how best describe the components of the arterial valves. It is hardly surprising, therefore, that similar uncertainties apply to concepts for their development. In this review, we describe the anatomy of the arterial valves as seen in the postnatal heart. We suggest that their working components are best described as leaflets, housed in supporting arterial sinuses. The roots surrounding the leaflets, which are hinged in semilunar fashion, can then be defined as extending from a virtual ring at their base to the sinutubular junction. We also discuss the problems related to definition of the valvar “annulus”. Understanding the development of the arterial roots, which are formed in the central part of the embryonic outflow tract, is facilitated by considering the outflow tract itself as possessing three components, as opposed to the traditional “conus” and “truncus”. These three parts can be described as being distal, intermediate, and proximal. The distal part is separated to form the intrapericardial arterial trunks, while the proximal part becomes the ventricular outflow tracts. It is the intermediate component that houses the developing arterial valves, and their supporting valvar sinuses. The distal parts of the cushions that separate the outflow tract into aortic and pulmonary components, along with the intercalated cushions, excavate to form the leaflets. The walls of the sinuses are formed by growth of non-myocardial tissues from the heart-forming area. We then show how these features can be used to interpret the anatomy and development of congenitally malformed arterial valves. Full article
(This article belongs to the Special Issue Semilunar Valve Development and Disease)

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