title: TGFβ and Wnt in cardiac outflow tract defects in offspring of diabetic pregnancies.
abstract: BACKGROUND
  Diabetes mellitus in pregnancy causes defects in infant heart, including the outflow tracts (OFTs). Development of the aorta and pulmonary artery, which are derived from the common OFT in the embryo, is regulated by the transforming growth factor β (TGFβ) and Wnt families, and can be perturbed by hyperglycemia-generated intracellular stress conditions. However, the underlying cellular and molecular mechanisms remain to be delineated.
  
  
  METHODS
  Female mice were induced diabetic with streptozotocin. Embryonic and fetal OFTs were examined morphologically and histologically. Cell proliferation was assessed using 5'-bromo-2'-deoxyuridine incorporation assay. Oxidative and endoplasmic reticulum (ER) stress markers and TGFβ factors were detected using immunohistochemistry. The expression of genes in the Wnt-signaling system was assessed using real-time reverse transcription polymerase chain reaction array. The role of activin-A in cell proliferation was addressed by treating embryos cultured in high glucose with activin-A.
  
  
  RESULTS
  Maternal diabetes caused complex abnormalities in the OFTs, including aortic and pulmonary stenosis and persistent truncus arteriosus. The development of the endocardial cushions was suppressed, manifested with insufficient cellularization of the tissues. Cell proliferation was significantly decreased under oxidative and ER stress conditions. The expression of genes in the Wnt signaling was significantly altered. Activin-A and Smad3 were found to be expressed in the OFT. Treatment with activin-A rescued cell proliferation in the endocardial cushions.
  
  
  CONCLUSIONS
  Maternal diabetes generates oxidative and ER stress conditions, suppresses TGFβ and Wnt signaling, inhibits cell proliferation and cellularization of the endocardial cushions, leading to OFT septal defects. Activin-A plays a role in hyperglycemia-suppressed proliferation of the endocardial cells.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhao
mesh_terms: D028341:Activins / Q000096:biosynthesis / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000196:embryology; D001024:Aortic Valve Stenosis / Q000473:pathology; D002302:Cardiac Output / Q000502:physiology; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000473:pathology*; D016640:Diabetes, Gestational / Q000473:pathology*; D046149:Embryo Culture Techniques; D004622:Embryo, Mammalian / Q000378:metabolism; D054089:Endocardial Cushions / Q000196:embryology; D059865:Endoplasmic Reticulum Stress; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005947:Glucose / Q000494:pharmacology; D006330:Heart Defects, Congenital / Q000473:pathology*; D006943:Hyperglycemia / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009432:Neural Crest / Q000196:embryology; D018384:Oxidative Stress; D011247:Pregnancy; D011651:Pulmonary Artery / Q000196:embryology; D011666:Pulmonary Valve Stenosis / Q000473:pathology; D051900:Smad3 Protein / Q000096:biosynthesis; D013311:Streptozocin; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014339:Truncus Arteriosus, Persistent / Q000473:pathology; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D028341:Activins; D013311:Streptozocin; D005947:Glucose
keywords: TGFβ; Wnt; cardiac defects; diabetic embryopathy; outflow tract