Search Results (10)

Cornelia de Lange Syndrome (CdLS) patients, who frequently carry a mutation in NIPBL, present an increased incidence of outflow tract (OFT)-related congenital heart defects (CHDs). Nipbl+/- mice recapitulate a number of phenotypic traits of CdLS patients, including a small body size and cardiac defects, but no study has specifically focused on the valves. Here, we show that adult Nipbl+/- mice present aortic valve thickening, a condition that has been associated with stenosis. During development, we observed that OFT septation and neural crest cell condensation was delayed in Nipbl+/- embryos. However, we did not observe defects in the deployment of the main lineages contributing to the semilunar valves. Indeed, endocardial endothelial-to-mesenchymal transition (EndMT), analysed via outflow tract explants, and neural crest migration, analysed via genetic lineage tracing, did not significantly differ in Nipbl+/- mice and their wild-type littermates. Our study provides the first direct evidence for valve formation defects in Nipbl+/- mice and points to specific developmental defects as an origin for valve disease in patients. Full article

A transgenic strain of pigs was created to express green fluorescent protein (GFP) ubiquitously using a pCAGG promoter. Here, we characterize GFP expression in the semilunar valves and great arteries of GFP-transgenic (GFP-Tg) pigs. Immunofluorescence was performed to visualize and quantify GFP expression and colocalization with nuclear staining. GFP expression was confirmed in both the semilunar valves and great arteries of GFP-Tg pigs compared to wild-type tissues (aorta, p = 0.0002; pulmonary artery, p = 0.0005; aortic valve; and pulmonic valve, p < 0.0001). The quantification of GFP expression in cardiac tissue allows this strain of GFP-Tg pigs to be used for future research in partial heart transplantation. Full article

Calcific aortic valve disease (CAVD) is a common cardiac defect, particularly in the aging population. While several risk factors, such as bi-leaflet valve structure and old age, have been identified in CAVD pathogenesis, molecular mechanisms resulting in this condition are still under active investigation. Bone morphogenetic protein signaling via the activin type I receptor (AcvRI) plays an important role during physiological and pathological processes involving calcification, e.g., bone formation and heterotopic ossification. In addition, AcvRI is required for normal cardiac valve development, yet its role in aortic valve disease, if any, is currently unknown. Here, we induced the expression of constitutively active AcvRI in developing mouse embryos in the endocardium and in cells at the valve leaflet–wall junction that are not of endocardium origin using the Nfac1Cre transgene. The mutant mice were born alive, but showed thickened aortic and pulmonary valve leaflets during the early postnatal period. Adult mutant mice developed aortic stenosis with high frequency, sclerotic aortic valves, and displayed Alcian Blue-positive hypertrophic chondrocyte-like cells at the leaflet–wall junction. Calcification was only seen with low penetrance. In addition, we observed that the expression levels of gene sets associated with inflammation-related cytokine signaling, smooth muscle cell contraction, and cGMP signaling were altered in the mutants when compared with those of the controls. This work shows that, in a mouse model, such continuous AcvRI activity in the Nfatc1Cre recombination domain results in pathological changes in the aortic valve structure and function. Full article

This Introduction provides both a short reflection on the scientific career of Adriana Gittenberger-de Groot and an overview of the papers that form the basis of this Special Issue giving them a proper perspective. The papers have as a central focus the outflow tract, and include contributions on development and pathology of the ventricles including AV valves, as well as developmental and pathomorphological aspects of the great arteries including semilunar valves and coronary arteries. Full article

Background: The outflow tract of crocodilians resembles that of birds and mammals as ventricular septation is complete. The arterial anatomy, however, presents with a pulmonary trunk originating from the right ventricular cavum, and two aortas originating from either the right or left ventricular cavity. Mixing of blood in crocodilians cannot occur at the ventricular level as in other reptiles but instead takes place at the aortic root level by a shunt, the foramen of Panizza, the opening of which is guarded by two facing semilunar leaflets of both bicuspid aortic valves. Methods: Developmental stages of Alligator mississipiensis, Crocodilus niloticus and Caiman latirostris were studied histologically. Results and Conclusions: The outflow tract septation complex can be divided into two components. The aorto-pulmonary septum divides the pulmonary trunk from both aortas, whereas the interaortic septum divides the systemic from the visceral aorta. Neural crest cells are most likely involved in the formation of both components. Remodeling of the endocardial cushions and both septa results in the formation of bicuspid valves in all three arterial trunks. The foramen of Panizza originates intracardially as a channel in the septal endocardial cushion. Full article

The aorta is not a rigid tube, it is an “organ” with lamellar units, consisting of elastic fibers, extracellular matrix and smooth muscle cells in between as parenchyma. Several diseases may occur in the natural history of the aorta, requiring replacement of both semilunar cusps and ascending aorta. They may be congenital defects, such as bicuspid aortic valve and isthmal coarctation with aortopathy; genetically determined, such as Marfan and William syndromes; degenerative diseases, such as atherosclerosis and medial necrosis with aortic dilatation, valve incompetence and dissecting aneurysm; inflammatory diseases such as Takayasu arteritis, syphilis, giant cell and IgM4 aortitis; neoplasms; and trauma. Aortic homografts from cadavers, including both the sinus portion with semilunar cusps and the tubular portion, are surgically employed to replace a native sick ascending aorta. However, the antigenicity of allograft cells, in the lamellar units and interstitial cells in the cusps, is maintained. Thus, an immune reaction may occur, limiting durability. After proper decellularization and 6 months’ implantation in sheep, endogenous cell repopulation was shown to occur in both the valve and aortic wall, including the endothelium, without evidence of inflammation and structural deterioration/calcification in the mid-term. The allograft was transformed into an autograft. Full article

Although in many ways the arterial and atrioventricular valves are similar, both being derived for the most part from endocardial cushions, we now know that the arterial valves and their surrounding structures are uniquely dependent on progenitors from both the second heart field (SHF) and neural crest cells (NCC). Here, we will review aspects of arterial valve development, highlighting how our appreciation of NCC and the discovery of the SHF have altered our developmental models. We will highlight areas of research that have been particularly instructive for understanding how the leaflets form and remodel, as well as those with limited or conflicting results. With this background, we will explore how this developmental knowledge can help us to understand human valve malformations, particularly those of the bicuspid aortic valve (BAV). Controversies and the current state of valve genomics will be indicated. Full article

Transforming growth factor beta3 (TGFB3) gene mutations in patients of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD1) and Loeys-Dietz syndrome-5 (LDS5)/Rienhoff syndrome are associated with cardiomyopathy, cardiac arrhythmia, cardiac fibrosis, cleft palate, aortic aneurysms, and valvular heart disease. Although the developing heart of embryos express Tgfb3, its overarching role remains unclear in cardiovascular development and disease. We used histological, immunohistochemical, and molecular analyses of Tgfb3^−/− fetuses and compared them to wildtype littermate controls. The cardiovascular phenotypes were diverse with approximately two thirds of the Tgfb3^−/− fetuses having one or more cardiovascular malformations, including abnormal ventricular myocardium (particularly of the right ventricle), outflow tract septal and alignment defects, abnormal aortic and pulmonary trunk walls, and thickening of semilunar and/or atrioventricular valves. Ventricular septal defects (VSD) including the perimembranous VSDs were observed in Tgfb3^−/− fetuses with myocardial defects often accompanied by the muscular type VSD. In vitro studies using TGFβ3-deficient fibroblasts in 3-D collagen lattice formation assays indicated that TGFβ3 was required for collagen matrix reorganization. Biochemical studies indicated the ‘paradoxically’ increased activation of canonical (SMAD-dependent) and noncanonical (MAP kinase-dependent) pathways. TGFβ3 is required for cardiovascular development to maintain a balance of canonical and noncanonical TGFβ signaling pathways. Full article

The beating heart is subject to intrinsic mechanical factors, exerted by contraction of the myocardium (stretch and strain) and fluid forces of the enclosed blood (wall shear stress). The earliest contractions of the heart occur already in the 10-somite stage in the tubular as yet unsegmented heart. With development, the looping heart becomes asymmetric providing varying diameters and curvatures resulting in unequal flow profiles. These flow profiles exert various wall shear stresses and as a consequence different expression patterns of shear responsive genes. In this paper we investigate the morphological alterations of the heart after changing the blood flow by ligation of the right vitelline vein in a model chicken embryo and analyze the extended expression in the endocardial cushions of the shear responsive gene Tgfbeta receptor III. A major phenomenon is the diminished endocardial-mesenchymal transition resulting in hypoplastic (even absence of) atrioventricular and outflow tract endocardial cushions, which might be lethal in early phases. The surviving embryos exhibit several cardiac malformations including ventricular septal defects and malformed semilunar valves related to abnormal development of the aortopulmonary septal complex and the enclosed neural crest cells. We discuss the results in the light of the interactions between several shear stress responsive signaling pathways including an extended review of the involved Vegf, Notch, Pdgf, Klf2, eNos, Endothelin and Tgfβ/Bmp/Smad networks. Full article

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