deficient signaling via alk2 (acvr1) leads to bicuspid aortic valve development缺陷信号通过alk2(acvr1)导致二叶主动脉瓣的发展.pdfVIP

Deficient Signaling via Alk2 (Acvr1) Leads to Bicuspid Aortic Valve Development 1 1¤ 2 1 Penny S. Thomas , Somyoth Sridurongrit , Pilar Ruiz-Lozano , Vesa Kaartinen * 1 Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, Michigan, United States of America, 2 Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America 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 con