Co-ordinating Notch, BMP, and TGF-β signaling during heart valve development

Congenital heart defects affect approximately 1–5 % of human newborns each year, and of these cardiac defects 20–30 % are due to heart valve abnormalities. Recent literature indicates that the key factors and pathways that regulate valve development are also implicated in congenital heart defects and valve disease. Currently, there are limited options for treatment of valve disease, and therefore having a better understanding of valve development can contribute critical insight into congenital valve defects and disease. There are three major signaling pathways required for early specification and initiation of endothelial-to-mesenchymal transformation (EMT) in the cardiac cushions: BMP, TGF-β, and Notch signaling. BMPs secreted from the myocardium set up the environment for the overlying endocardium to become activated; Notch signaling initiates EMT; and both BMP and TGF-β signaling synergize with Notch to promote the transition of endothelia to mesenchyme and the mesenchymal cell invasiveness. Together, these three essential signaling pathways help form the cardiac cushions and populate them with mesenchyme and, consequently, set off the cascade of events required to develop mature heart valves. Furthermore, integration and cross-talk between these pathways generate highly stratified and delicate valve leaflets and septa of the heart. Here, we discuss BMP, TGF-β, and Notch signaling pathways during mouse cardiac cushion formation and how they together produce a coordinated EMT response in the developing mouse valves.     

Cardiovascular development: towards biomedical applicability

During cardiogenesis, the epicardium grows from the proepicardial organ to form the outermost layer of the early heart. Part of the epicardium undergoes epithelial-mesenchymal transformation, and migrates into the myocardium. These epicardium-derived cells differentiate into interstitial fibroblasts, coronary smooth muscle cells, and perivascular fibroblasts. Moreover, epicardium-derived cells are important regulators of formation of the compact myocardium, the coronary vasculature, and the Purkinje fiber network, thus being essential for proper cardiac development. The fibrous structures of the heart such as the fibrous heart skeleton and the semilunar and atrioventricular valves also depend on a contribution of these cells during development. We hypothesise that the essential properties of epicardium-derived cells can be recapitulated in adult diseased myocardium. These cells can therefore be considered as a novel source of adult stem cells useful in clinical cardiac regeneration therapy.     

Monoamine-containing cells in atrioventricular valves of the opossum heart

Summary Using a specific technique for biogenic amines, similar cells to those described as small intense fluorescent (SIF) cells were identified in the atrioventricular valves of the opossum heart. It is suggested that these cells, under neural control, may secrete amines.     

Ultrastructural localization of microfibrillar fibulin-1 and fibulin-2 during heart development indicates a switch in molecular associations

The microfibrillar proteins fibulin-1 and fibulin-2 were previously identified as prominent components of the endocardial cushion tissue (ECT) during heart development and shown to persist in adult valves and septa. Immunogold staining has now been used to compare their localization in embryonic (days 9–11) and adult mouse heart with that of fibronectin and the chondroitin sulphate proteoglycan versican. All four proteins were deposited in the ECT, which consists of a hyaluronan-rich, mainly unstructured matrix, but were barely detectable in myocardial basement membranes or within endocardial cells. Digestion with hyaluronate lyase selectively released the fibulins and versican but not fibronectin from the ECT. Yet neither of the two fibulins bound to hyluronan in solid-phase assays, in contrast to versican. In the adult heart valve, all four proteins could be detected close to cross-striated collagen fibrils or microfibrils, but only versican was lost upon exposure to hyaluronate lyase. The data indicate that fibulins are associated with the hyaluronan-matrix of ECT through a bridge of versican, but that this association changes upon valve development to another supramolecular, presumably microfibrillar organization based on fibronectin and/or fibrillins. Received 3 April 1998; accepted 8 April 1998     

Cardiac and circulatory control in decapod Crustacea with comparisons to molluscs

Summary In this review I will attempt to identify the circulatory requirements a decapod is likely to encounter and how the heart is controlled to meet these demands. The decapod heart has been designed as an autonomous system endowed with an intrinsic autorhythmic pacemaker ganglion. Muscle fibers are multiply-innervated and capable of producing regenerative action potentials. This vitally important organ has been designed to be nearly fail-safe. Stroke volume is more important than heart rate in determining cardiac output. Stretch sensitivity of the cardiac ganglion and of the myocardium as well as extrinsic nervous and hormonal modulation of the heart can all contribute to changes in stroke volume. It may be advantageous to an animal to switch the circulation between various vascular beds to meet changing perfusion demands. Neuronal and hormonal mechanisms have been identified which exert differential control of the cardioarterial valves, but it is not known whether switching does occur and if so whether these valves participate in the process. Changes in peripheral resistance can also redirect circulatory flow. The circulatory and ventilatory systems demonstrate coordinated rate changes which suggest that the heart is responding to meet changing ventilatory performance requirements. This coupling is controlled both by the hydrostatic pressure pulses generated within the branchial chambers and by common higher level nervous inputs. Comparisons of the cardiovascular systems of crustaceans and molluscs, based on the papers presented at this symposium, are high-lighted.     

The Purkinje fiber-myocardial cell region in the goat heart as studied by combined scanning electron microscopy and chemical digestion

The 3-dimensional architecture of the junctional region between Purkinje fibers and ordinary myocardial cells has been closely studied by combined scanning electron microscopy and chemical digestion in the goat heart. It was revealed that the Purkinje fibers forming the terminal arborization of the atrioventricular bundle are followed by transitional cells which are in contact with ordinary myocardial cells.     

The Purkinje fiber-myocardial cell region in the goat heart as studied by combined scanning electron microscopy and chemical digestion

Summary The 3-dimensional architecture of the junctional region between Purkinje fibers and ordinary myocardial cells has been closely studied by combined scanning electron microscopy and chemical digestion in the goat heart. It was revealed that the Purkinje fibers forming the terminal arborization of the atrioventricular bundle are followed by transitional cells which are in contact with ordinary myocardial cells.Acknowledgment. We wish to thank Professor M. Murakami and Professor K. Yamada for encouraging this study.     

Über die Reaktion der höheren und tieferen Reizbildungszentren des isolierten Herzens auf Temperatursenkung

Summary In the isolated rabbit heart perfused by the Langendorff method total heart block has been produced by section of the His bundle. The influence of cooling of the perfusion fluid upon higher and lower automatic centers was studied. The sinoauricular pacemaker responded to cooling with a much greater decrease of the heart rate than did the ventricular automatism. The responsiveness of the atrioventricular node to cooling lay between that of the two others.     

Enhancement of vertebrate cardiogenesis by a lectin from perivitelline fluid of horseshoe crab embryo

Cardiac myocytes are the first cells to differentiate during the development of a vertebrate embryo. A wide variety of molecules take part in various steps in this process. While exploring biologically active molecules from marine sources, we found that a constituent of perivitelline fluid from embryos of the Indian horseshoe crab can enhance growth and differentiation of chick embryonic heart. We have purified the factor and identified the cardiac promoting molecule to be a novel lectin. We show that this molecule influences cardiac development by increasing the number of cells constituting the heart and by modulating the expression of several cardiac development regulatory genes in chick embryos. Using mouse embryonic stem cells we show that the cardiac myocyte-enhancing capacity of this molecule extends to mammals and its effects can be blocked using methylated sugars. This molecule may prove to be an important tool in the study of cardiomyocyte differentiation.     

Very large common fragile site genes and their potential role in cancer development

Common fragile sites (CFSs) are large chromosomal regions that are hot-spots for alterations especially within cancer cells. The three most frequently expressed CFS regions (FRA3B, FRA16D and FRA6E) contain genes that span extremely large genomic regions (FHIT, WWOX and PARK2, respectively), and these genes were found to function as important tumor suppressors. Many other CFS regions contain extremely large genes that are also targets of alterations in multiple cancers, but none have yet been demonstrated to function as tumor suppressors. The loss of expression of just FHIT or WWOX has been found to be associated with a worse overall clinical outcome. Studies in different cancers have revealed that some cancers have decreased expression of multiple large CFS genes. This loss of expression could have a profound phenotypic effect on these cells. In this review, we will summarize the known large common fragile site genes and discuss their potential relationship to cancer development.