title: Conditional inactivation of TGF-β type II receptor in smooth muscle cells and epicardium causes lethal aortic and cardiac defects.
abstract: To understand the role of TGF-β signaling in cardiovascular development, we generated mice with conditional deletion of the TGF-β type II receptor (TβRII) gene (Tgfbr2) in cells expressing the smooth muscle cell-specific protein SM22α. The SM22α promoter was active in tissues involved in cardiovascular development: vascular smooth muscle cells (VSMCs), epicardium and myocardium. All SM22-Cre(+/-)/Tgfbr2 (flox/flox) embryos died during the last third of gestation. About half the mutant embryos exhibited heart defects (ventricular myocardium hypoplasia and septal defects). All mutant embryos displayed profound vascular abnormalities in the descending thoracic aorta (irregular outline and thickness, occasional aneurysms and elastic fiber disarray). Restriction of these defects to the descending thoracic aorta occurred despite similar levels of Tgfbr2 invalidation in the other portions of the aorta, the ductus arteriosus and the pulmonary trunk. Immunocytochemistry identified impairment of VSMC differentiation in the coronary vessels and the descending thoracic aorta as crucial for the defects. Ventricular myocardial hypoplasia, when present, was associated to impaired α-SMA differentiation of the epicardium-derived coronary VSMCs. Tgfbr2 deletion in the VSMCs of the descending thoracic aorta diminished the number of α-SMA-positive VSMC progenitors in the media at E11.5 and drastically decreased tropoelastin (from E11.5) and fibulin-5 (from E.12.5) synthesis and/or deposition. Defective elastogenesis observed in all mutant embryos and the resulting dilatation and probable rupture of the descending thoracic aorta might explain the late embryonic lethality. To conclude, during mouse development, TGF-β plays an irreplaceable role on the differentiation of the VSMCs in the coronary vessels and the descending thoracic aorta.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM ERI 22), Université de Lyon 1 (EA 4173) and IFR Lyon-Est, 69373, Lyon cedex 08, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Langlois
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hneino
authors.forename: Lamia
authors.initials: L
authors.lastname: Bouazza
authors.forename: Ara
authors.initials: A
authors.lastname: Parlakian
authors.forename: Takako
authors.initials: T
authors.lastname: Sasaki
authors.forename: Giampiero
authors.initials: G
authors.lastname: Bricca
authors.forename: Jacques Yuan
authors.initials: JY
authors.lastname: Li
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D004547:Elastic Tissue / Q000473:pathology; D004549:Elastin / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D010496:Pericardium / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016326:Extracellular Matrix Proteins; C120769:Fbln5 protein, mouse; D008840:Microfilament Proteins; D009124:Muscle Proteins; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C051615:transgelin; D004549:Elastin; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II