title: Deficient signaling via Alk2 (Acvr1) leads to bicuspid aortic valve development.
abstract: Bicuspid aortic valve (BAV) is the most common congenital cardiac anomaly in humans. Despite recent advances, the molecular basis of BAV development is poorly understood. Previously it has been shown that mutations in the Notch1 gene lead to BAV and valve calcification both in human and mice, and mice deficient in Gata5 or its downstream target Nos3 have been shown to display BAVs. Here we show that tissue-specific deletion of the gene encoding Activin Receptor Type I (Alk2 or Acvr1) in the cushion mesenchyme results in formation of aortic valve defects including BAV. These defects are largely due to a failure of normal development of the embryonic aortic valve leaflet precursor cushions in the outflow tract resulting in either a fused right- and non-coronary leaflet, or the presence of only a very small, rudimentary non-coronary leaflet. The surviving adult mutant mice display aortic stenosis with high frequency and occasional aortic valve insufficiency. The thickened aortic valve leaflets in such animals do not show changes in Bmp signaling activity, while Map kinase pathways are activated. Although dysfunction correlated with some pro-osteogenic differences in gene expression, neither calcification nor inflammation were detected in aortic valves of Alk2 mutants with stenosis. We conclude that signaling via Alk2 is required for appropriate aortic valve development in utero, and that defects in this process lead to indirect secondary complications later in life.
authors.affiliation: Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Penny S
authors.initials: PS
authors.lastname: Thomas
authors.forename: Somyoth
authors.initials: S
authors.lastname: Sridurongrit
authors.forename: Pilar
authors.initials: P
authors.lastname: Ruiz-Lozano
authors.forename: Vesa
authors.initials: V
authors.lastname: Kaartinen
mesh_terms: D030201:Activin Receptors, Type I / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001021:Aortic Valve / Q000002:abnormalities* / Q000196:embryology / Q000378:metabolism; D049109:Cell Proliferation; D054089:Endocardial Cushions / Q000378:metabolism; D005260:Female; D050992:GATA5 Transcription Factor / Q000378:metabolism / Q000502:physiology; D015870:Gene Expression; D006345:Heart Septal Defects, Ventricular / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D006349:Heart Valve Diseases / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011995:Recombination, Genetic; D055758:SOX9 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000378:metabolism; D019063:Tenascin / Q000378:metabolism; D053675:Versicans / Q000378:metabolism
chemical_list: D050992:GATA5 Transcription Factor; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D020825:T-Box Domain Proteins; C486013:Tbx20 protein, mouse; D019063:Tenascin; C508323:Vcan protein, mouse; D053675:Versicans; D030201:Activin Receptors, Type I; C498943:Acvr1 protein, mouse