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Biomedical subjects

Daniel G M Molin

Publications and source records attributed to Daniel G M Molin.

7 recordsLinked to original sources
PubMed2007

Exposure of neural crest cells to elevated glucose leads to congenital heart defects, an effect that can be prevented by N-acetylcysteine.

BACKGROUND: Diabetes mellitus during pregnancy increases the risk for congenital heart disease in the offspring. The majority of the cardiovascular malformations occur in the outflow tract and pharyngeal arch arteries, where neural crest cells are essential for normal development. We studied the effects of specific exposure of neural crest cells to elevated glucose on heart development. Antioxidants reduce the damaging effect of glucose on neural crest cells in vitro; therefore, we investigated the effect of supplementing N-acetylcysteine in vivo. METHODS: Cardiac neural crest of HH 8-12 chicken embryos was directly exposed by a single injection in the neural tube with 30 mM D-glucose (or 30 mM L-glucose as a control). To examine the effect of a reduction in oxidative stress, we added 2 mM N-acetylcysteine to the injected D-glucose. RESULTS: Exposure of neural crest cells to elevated D-glucose-induced congenital heart malformations in 82% of the embryos. In the embryos injected with L-glucose, only 9% developed a heart malformation. As expected, all malformations were located in the outflow tract and pharyngeal arch arteries. The frequency of heart malformations decreased from 82% to 27% when 2 mM N-acetylcysteine was added to the injected D-glucose. CONCLUSIONS: These data are the first to confirm that the vulnerability of neural crest cells to elevated glucose induces congenital heart malformations. The fact that N-acetylcysteine limits the teratogenicity of glucose implies that its damaging effect is mediated by an increase of oxidative stress in the neural crest cells.

Acetylcysteine↗
PubMed2004

Transforming growth factor beta-SMAD2 signaling regulates aortic arch innervation and development.

Aortic arch interruptions in humans and animal models are mainly caused by aberrant development of the fourth pharyngeal arch artery. Little is known about the maturation of this vessel during normal and abnormal development, which is the subject of this study. Tgfbeta2 knockout mice that present with fourth artery defects have been associated with defective neural crest cell migration. In this study, we concentrated on pharyngeal arch artery development during developmental days 12.5 to 18.5, focusing on neural crest cell migration using a Wnt1-Cre by R26R neural crest cell reporter mouse. Fourth arch artery maturation was studied with antibodies directed against smooth muscle alpha-actin and neural NCAM-1 and RMO-270. For diminished transforming growth factor beta (TGF-beta) signaling, SMAD2 and fibronectin have been analyzed. Neural crest migration and differentiation into smooth muscle cells is unaltered in mutants, regardless of the cardiovascular defect found; however, innervation of the fourth arch artery is affected. Absent staining for nuclear SMAD2, NCAM-1, and RMO-270 in the fourth artery in mutant coincides with severe defects of this segment. Likewise, fibronectin expression is diminished in these cases. From these data we conclude the following: (1) neural crest cell migration is not a common denominator in cardiovascular defects of Tgfbeta2-/- mice; (2) fourth arch artery maturation is a complex process involving innervation; and (3) TGF-beta2 depletion diminishes SMAD2-signaling in the fourth arch artery and coincides with reduced vascular NCAM-1 expression and neural innervation of this artery. We hypothesize that disturbed maturation of the fourth pharyngeal arch artery, and especially abrogated vascular innervation, will result in fourth arch interruptions.

Abnormalities, Multiple↗
PubMed2004

The neural crest is contiguous with the cardiac conduction system in the mouse embryo: a role in induction?

In this study we present data on the spatial relationship between neural crest-derived cells (NCC) and the specialized cardiac conduction system (CCS) in the developing murine heart. Using Wnt1-Cre/R26R conditional reporter mice that express beta-galactosidase from ROSA26 upon Cre-mediated recombination, two populations of NCC are seen: one migrates through the arterial pole and contributes to the bundle branches, whereas the second population enters by way of the venous pole and provides cells to the sinoatrial and atrioventricular node areas. The CCS/ lacZ construct is found in the myocardium of the early embryonic heart and afterward only persists in the definitive CCS and is acknowledged as a reporter for the developing conduction system. The contiguous expression of both reporters is suggestive for a potential role of cardiac NCC in the induction of the final differentiation of the CCS.

Animals↗
PubMed2004

Changing intracellular compartmentalization of beta-galactosidase in the ROSA26 reporter mouse during embryonic development: a light- and electron-microscopic study.

The beta-geo (LacZ) reporter gene encodes for beta-galactosidase (beta-gal) in all cells of the ROSA26 mouse during embryonic development. As such, beta-gal activity constitutes an excellent marker for in situ labeling of expressing cells. However, the intracellular distribution of beta-gal differs between cells, and changes during embryonic development. Therefore, we studied LacZ-encoded beta-gal using light and electron microscopy in the heart, lung, liver, and small intestine on days 13 and 16 of gestation, and the kidney on day 16 of gestation in ROSA26 mice. The Bluo-gal method was carried out under standardized conditions, including fixation, washing, and incubation procedures. Intracellular beta-gal staining is encountered in a combination of membranous compartments, including the nuclear envelope, the endoplasmic reticulum, and the plasma membrane. Its exact localization depends on the cell type and is regulated during development. Therefore, one must take the compartmental transition of intracellular beta-gal staining into consideration when interpreting results obtained from experiments using ROSA26 mice.

Animals↗
PubMed2003

VEGF: a modifier of the del22q11 (DiGeorge) syndrome?

Hemizygous deletion of chromosome 22q11 (del22q11) causes thymic, parathyroid, craniofacial and life-threatening cardiovascular birth defects in 1 in 4,000 infants. The del22q11 syndrome is likely caused by haploinsufficiency of TBX1, but its variable expressivity indicates the involvement of additional modifiers. Here, we report that absence of the Vegf164 isoform caused birth defects in mice, reminiscent of those found in del22q11 patients. The close correlation of birth and vascular defects indicated that vascular dysgenesis may pathogenetically contribute to the birth defects. Vegf interacted with Tbx1, as Tbx1 expression was reduced in Vegf164-deficient embryos and knocked-down vegf levels enhanced the pharyngeal arch artery defects induced by tbx1 knockdown in zebrafish. Moreover, initial evidence suggested that a VEGF promoter haplotype was associated with an increased risk for cardiovascular birth defects in del22q11 individuals. These genetic data in mouse, fish and human indicate that VEGF is a modifier of cardiovascular birth defects in the del22q11 syndrome.

Animals↗
PubMed2003

Transforming growth factor beta in cardiovascular development and function.

Transforming growth factor betas (TGFbetas) are pleiotropic cytokines involved in many biological processes. Genetic engineering and tissue explanation studies have revealed specific non-overlapping roles for TGFbeta ligands and their signaling molecules in development and in normal function of the cardiovascular system in the adult. In the embryo, TGFbetas appear to be involved in epithelial-mesenchymal transformations (EMT) during endocardial cushion formation, and in epicardial epithelial-mesenchymal transformations essential for coronary vasculature, ventricular myocardial development and compaction. In the adult, TGFbetas are involved in cardiac hypertrophy, vascular remodeling and regulation of the renal renin-angiotensin system. The evidence for TGFbeta activities during cardiovascular development and physiologic function will be given and areas which need further investigation will be discussed.

Animals↗