Trichloroethylene inhibits development of embryonic heart valve precursors in vitro.
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Previous epidemiological studies with humans and laboratory studies with chickens and rats linked trichloroethylene (TCE) exposure to cardiac defects. Although the cardiac defects in humans and laboratory animals produced by TCE are diverse, a majority of them involves valvular and septal structures. Progenitors of the valves and septa are formed by an epithelial-mesenchymal cell transformation of endothelial cells in the atrioventricular (AV) canal and outflow tract areas of the heart. Based on these studies, we hypothesized that TCE might cause cardiac valve and septa defects by specifically perturbing epithelial-mesenchymal cell transformation. We tested this hypothesis using an in vitro chick-AV canal culture model. This study shows that TCE affected several elements of epithelial-mesenchymal cell transformation. In particular, TCE blocked the endothelial cell-cell separation process that is associated with endothelial activation. Moreover, TCE inhibited mesenchymal cell formation throughout the concentration range tested (50-250 ppm). In contrast, TCE had no effect on the cell migration rate of the fully formed mesenchymal cells. Finally, the expression of 3 proteins (selected as molecular markers of epithelial-mesenchymal cell transformation) was analyzed in untreated and TCE-treated cultures. TCE inhibited the expression of the transcription factor Mox-1 and extracellular matrix (ECM) protein fibrillin 2. In contrast, TCE had no effect on the expression of alpha-smooth muscle actin. These data suggest that TCE may cause cardiac valvular and septal malformations by inhibiting endothelial separation and early events of mesenchymal cell formation in the heart. (+info)
Surgical management of mitral regurgitation after repair of endocardial cushion defects: early and midterm results.
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BACKGROUND: Mitral regurgitation (MR) represents the principal indication for reoperation in patients after repair of atrioventricular septal defects (AVSD). Reports of mitral valvuloplasty (MVP) in such patients are few; the alternative, mitral valve replacement (MVR), necessitates commitment to future valve replacement and long-term anticoagulation. We sought to determine the outcome of those patients who underwent either MVP or MVR between January 1, 1988, and December 31, 1998, for significant MR after repair of AVSD. Furthermore, we sought to identify (a) morphological predictors necessitating MVR, and (b) predictors of future reoperation within the MVP group. METHODS AND RESULTS: Retrospective review of clinical, operative, and echocardiographic data were performed. There were 46 patients identified (37 MVP and 9 MVR). The median age at initial AVSD repair was 0.6 years, and the age at subsequent mitral valve operation was 2.8 years. The early postoperative mortality rate was 2.2%, and survival at 1 and 10 years was 89.9% and 86.6%, respectively. A high rate of complete heart block was noted within the MVR group (37.5%). Freedom from later mitral valve reoperation for both groups was similar. No significant morphological predictors necessitating MVR were found. Predictors of reoperation within the MVP group included the presence of moderate or worse MR in the early postoperative period. In both groups New York Heart Association class, degree of MR, growth, and ventricular volumes improved. CONCLUSIONS: Mitral valve surgery significantly improves clinical status, with a sustained improvement in ventricular chamber size. MR can be successfully managed in patients after repair of AVSD independent of morphological type. Overall survival is acceptable, and further reoperation within the MVP group is influenced by early outcome of repair. (+info)
Unusual association of hypertrophic cardiomyopathy with complete atrioventricular canal defect and Down syndrome.
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Hypertrophic cardiomyopathy typically presents as an isolated cardiac lesion. Transient hypertrophic cardiomyopathy in infancy has been described as a result of exposure to maternal metabolic disorders or to corticosteroids. In addition, hypertrophic cardiomyopathy has been described in association with genetic syndromes and, in rare cases, as a primary lesion associated with other congenital heart defects. We describe the unusual association of hypertrophic cardiomyopathy and complete atrioventricular canal defect in an infant with trisomy 21. (+info)
Retinoic acid administration is associated with changes in the extracellular matrix and cardiac mesenchyme within the endocardial cushion.
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Retinoic acid has been associated with a number of cardiac defects, some of which seem to be related to changes in the endocardial cushions. Studies in mice and older chick embryos have suggested that these defects may be associated with a decrease in mesenchymal cell formation within the cushion. In a previous report we showed that retinoic acid lowered the number of mesenchymal cells in a culture bioassay of mesenchyme formation and that this response was due to retinoic acid modifying the production of particulate matrix from the myocardium. In this study, we have extended these observations to the embryo by implanting a retinoic acid coated bead into the embryo and examined the effect on cardiac mesenchyme formation and in the production of the particulate matrix. In all cases the addition of retinoic acid resulted in a decrease in the number of mesenchymal cells invading the endocardial cushions. In addition retinoic acid increased the production of hLAMP-1 and fibronectin but not transferrin, confirming our earlier report. Finally, we measured the volume of the cushion and calculated the cell density of both the inferior and superior cushions. The results suggest that the superior cushion is more sensitive to retinoic acid treatment than the inferior cushion. Collectively, these results support our earlier work that suggests that the mechanism of retinoic acid cardiac abnormalities involves a disruption in the production of particulate matrix from the myocardium and a subsequent decrease in cardiac mesenchyme cells that results in a malformed cardiac cushions. (+info)
Hyperplastic conotruncal endocardial cushions and transposition of great arteries in perlecan-null mice.
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Perlecan is a heparan-sulfate proteoglycan abundantly expressed in pericellular matrices and basement membranes during development. Inactivation of the perlecan gene in mice is lethal at two developmental stages: around E10 and around birth. We report a high incidence of malformations of the cardiac outflow tract in perlecan-deficient embryos. Complete transposition of great arteries was diagnosed in 11 out of 15 late embryos studied (73%). Three of these 11 embryos also showed malformations of semilunar valves. Mesenchymal cells in the outflow tract were abnormally abundant in mutant embryos by E9.5, when the endocardial-mesenchymal transformation starts in wild-type embryos. At E10.5, mutant embryos lacked well-defined spiral endocardial ridges, and the excess of mesenchymal cells obstructed sometimes the outflow tract lumen. Most of this anomalous mesenchyme expressed the smooth muscle cell-specific alpha-actin isoform, a marker of the neural crest in the outflow tract of the mouse. In wild-type embryos, perlecan is present in the basal surface of myocardium and endocardium, as well as surrounding presumptive neural crest cells. We suggest that the excess of mesenchyme at the earlier stages of conotruncal development precludes the formation of the spiral ridges and the rotation of the septation complex in order to achieve a concordant ventriculoarterial connection. The observed mesenchymal overpopulation might be due to an uncontrolled migration of neural crest cells, which would arrive prematurely to the heart. Thus, perlecan is involved in the control of the outflow tract mesenchymal population size, underscoring the importance of the extracellular matrix in cardiac morphogenesis. (+info)
Elevated glucose inhibits VEGF-A-mediated endocardial cushion formation: modulation by PECAM-1 and MMP-2.
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Atrioventricular (AV) septal defects resulting from aberrant endocardial cushion (EC) formation are observed at increased rates in infants of diabetic mothers. EC formation occurs via an epithelial-mesenchymal transformation (EMT), involving transformation of endocardial cells into mesenchymal cells, migration, and invasion into extracellular matrix. Here, we report that elevated glucose inhibits EMT by reducing myocardial vascular endothelial growth factor A (VEGF-A). This effect is reversed with exogenous recombinant mouse VEGF-A165, whereas addition of soluble VEGF receptor-1 blocks EMT. We show that disruption of EMT is associated with persistence of platelet endothelial cell adhesion molecule-1 (PECAM-1) and decreased matrix metalloproteinase-2 (MMP-2) expression. These findings correlate with retention of a nontransformed endocardial sheet and lack of invasion. The MMP inhibitor GM6001 blocks invasion, whereas explants from PECAM-1 deficient mice exhibit MMP-2 induction and normal EMT in high glucose. PECAM-1-negative endothelial cells are highly motile and express more MMP-2 than do PECAM-1-positive endothelial cells. During EMT, loss of PECAM-1 similarly promotes single cell motility and MMP-2 expression. Our findings suggest that high glucose-induced inhibition of AV cushion morphogenesis results from decreased myocardial VEGF-A expression and is, in part, mediated by persistent endocardial cell PECAM-1 expression and failure to up-regulate MMP-2 expression. (+info)
Loss of distinct arterial and venous boundaries in mice lacking endoglin, a vascular-specific TGFbeta coreceptor.
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Several characteristic morphological and functional differences distinguish arteries from veins. It was thought that hemodynamic forces shaped these differences; however, increasing evidence suggests that morphogenetic programs play a central role in blood vessel differentiation. Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia characterized by the inappropriate fusion of arterioles with venules. The genes implicated in this disease, ALK1 and endoglin, may be involved in defining the fundamental boundaries between arteries and veins. We previously showed that mice lacking Alk1 lost structural, molecular, and functional distinctions between arteries and veins. Here, we report that mice lacking endoglin develop arterial-venous malformations and fail to confine intraembryonic hematopoiesis to arteries. In contrast to Alk1 mutants, endoglin mutants do not show profound vessel dilation or downregulation of arterial ephrinB2. Finally, our data indicate that a failure in cardiac cushion formation observed in both strains may be secondary to the peripheral vasculature defect. The phenotypic similarities, yet reduced severity, implicates endoglin as an accessory coreceptor that specifically modulates Alk1 signaling. We propose that endoglin and Alk1 are necessary for the maintenance of distinct arterial-venous vascular beds and that attenuation of the Alk1 signaling pathway is the precipitating event in the etiology of HHT. (+info)
Foxp1 regulates cardiac outflow tract, endocardial cushion morphogenesis and myocyte proliferation and maturation.
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We have recently described a new subfamily of Fox genes, Foxp1/2/4, which are transcriptional repressors and are thought to regulate important aspects of development in several tissues, including the lung, brain, thymus and heart. Here, we show that Foxp1 is expressed in the myocardium as well as the endocardium of the developing heart. To further explore the role of Foxp1 in cardiac development, we inactivated Foxp1 through gene targeting in embryonic stem cells. Foxp1 mutant embryos have severe defects in cardiac morphogenesis, including outflow tract septation and cushion defects, a thin ventricular myocardial compact zone caused by defects in myocyte maturation and proliferation, and lack of proper ventricular septation. These defects lead to embryonic death at E14.5 and are similar to those observed in other mouse models of congenital heart disease, including Sox4 and Nfatc1 null embryos. Interestingly, expression of Sox4 in the outflow tract and cushions of Foxp1 null embryos is significantly reduced, while remodeling of the cushions is disrupted, as demonstrated by reduced apoptosis and persistent Nfatc1 expression in the cushion mesenchyme. Our results reveal a crucial role for Foxp1 in three aspects of cardiac development: (1) outflow tract development and septation, (2) tissue remodeling events required for cardiac cushion development, and (3) myocardial maturation and proliferation. (+info)