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

Yidong Wang, Bingruo Wu, Emily Farrar, Wendy Lui, Pengfei Lu, Donghong Zhang, Christina M. Alfieri, Kai Mao, Ming Chu, Di Yang, Di Xu, Michael Rauchman, Verdon Taylor, Simon J. Conway, Katherine E. Yutzey, Jonathan T. Butcher, Bin Zhou

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

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 Tnfa 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.

Original languageEnglish (US)
Pages (from-to)675-686
Number of pages12
JournalEuropean Heart Journal
Volume38
Issue number9
DOIs
StatePublished - Mar 1 2017

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Keywords

  • Congenital anomalies of arterial valves
  • Notch
  • TNF
  • Valvar aortic stenosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Wang, Y., Wu, B., Farrar, E., Lui, W., Lu, P., Zhang, D., Alfieri, C. M., Mao, K., Chu, M., Yang, D., Xu, D., Rauchman, M., Taylor, V., Conway, S. J., Yutzey, K. E., Butcher, J. T., & Zhou, B. (2017). Notch-TNF signalling is required for development and homeostasis of arterial valves. European Heart Journal, 38(9), 675-686. https://doi.org/10.1093/eurheartj/ehv520