Notch-Tnf signalling is required for development and homeostasis of arterial valves

Wang, Yidong and Wu, Bingruo and Farrar, Emily and Lui, Wendy and Lu, Pengfei and Zhang, Donghong and Alfieri, Christina M. and Mao, Kai and Chu, Ming and Yang, Di and Xu, Di and Rauchman, Michael and Taylor, Verdon and Conway, Simon J. and Yutzey, Katherine E. and Butcher, Jonathan T. and Zhou, Bin. (2017) Notch-Tnf signalling is required for development and homeostasis of arterial valves. European Heart Journal, 38 (9). pp. 675-686.

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Official URL: https://edoc.unibas.ch/62478/

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Aims Congenital anomalies of arterial valves are common birth defects, leading to valvar stenosis. With no pharmaceutical treatment that can prevent the disease progression, prosthetic replacement is the only choice of treatment, incurring considerable morbidity and mortality. Animal models presenting localized anomalies and stenosis of congenital arterial valves similar to that of humans are critically needed research tools to uncover developmental molecular mechanisms underlying this devastating human condition. Methods and results We generated and characterized mouse models with conditionally altered Notch signalling in endothelial or interstitial cells of developing valves. Mice with inactivation of Notch1 signalling in valvar endothelial cells (VEC) developed congenital anomalies of arterial valves including bicuspid aortic valves and valvar stenosis. Notch1 signalling in VEC was required for repressing proliferation and activating apoptosis of valvar interstitial cells (VIC) after endocardial- to-mesenchymal transformation (EMT). We showed that Notch signalling regulated Tnf alpha expression in vivo, and Tnf signalling was necessary for apoptosis of VIC and post-EMT development of arterial valves. Furthermore, activation or inhibition of Notch signalling in cultured pig aortic VEC-promoted or suppressed apoptosis of VIC, respectively. Conclusion We have now met the need of critical animal models and shown that Notch-Tnf signalling balances proliferation and apoptosis for post-EMT development of arterial valves. Our results suggest that mutations in its components may lead to congenital anomaly of aortic valves and valvar stenosis in humans.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Anatomy > Embryology and Stem Cell Biology (Taylor)
UniBasel Contributors:Taylor, Verdon
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Oxford University Press
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:04 Aug 2020 14:13
Deposited On:04 Aug 2020 14:13

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