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


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 Tnfα 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.


CONCLUSIONS
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.
Department of Genetics, Pediatrics, and Medicine (Cardiology), Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine, Price 420, 1301 Morris Park Avenue, Bronx, NY 14061, USA.
Yidong
Y
Wang
Department of Genetics, Pediatrics, and Medicine (Cardiology), Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine, Price 420, 1301 Morris Park Avenue, Bronx, NY 14061, USA.
Bingruo
B
Wu
Department of Biomedical Engineering, Cornell University, Ithaca, NY, USA.
Emily
E
Farrar
Department of Genetics, Pediatrics, and Medicine (Cardiology), Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine, Price 420, 1301 Morris Park Avenue, Bronx, NY 14061, USA.
Wendy
W
Lui
Department of Genetics, Pediatrics, and Medicine (Cardiology), Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine, Price 420, 1301 Morris Park Avenue, Bronx, NY 14061, USA.
Pengfei
P
Lu
Department of Genetics, Pediatrics, and Medicine (Cardiology), Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine, Price 420, 1301 Morris Park Avenue, Bronx, NY 14061, USA.
Donghong
D
Zhang
Division of Molecular Cardiovascular Biology, Cincinnati Children's Medical Centre, Cincinnati, OH, USA.
Christina M
CM
Alfieri
Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, USA.
Kai
K
Mao
Department of Medicine and Geriatrics (Cardiology), First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
Ming
M
Chu
Department of Medicine and Geriatrics (Cardiology), First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
Di
D
Yang
Department of Medicine and Geriatrics (Cardiology), First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
Di
D
Xu
Department of Internal Medicine, Saint Louis University, St. Louis, MO, USA.
Michael
M
Rauchman
Department of Biomedicine, University of Basel, Basel, Switzerland.
Verdon
V
Taylor
Department of Paediatrics, Indiana University, Indianapolis, IN, USA.
Simon J
SJ
Conway
Division of Molecular Cardiovascular Biology, Cincinnati Children's Medical Centre, Cincinnati, OH, USA.
Katherine E
KE
Yutzey
Department of Biomedical Engineering, Cornell University, Ithaca, NY, USA.
Jonathan T
JT
Butcher
Department of Genetics, Pediatrics, and Medicine (Cardiology), Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine, Price 420, 1301 Morris Park Avenue, Bronx, NY 14061, USA.|Department of Medicine and Geriatrics (Cardiology), First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
Bin
B
Zhou
D000818:Animals; D001021:Aortic Valve / Q000002:abnormalities; D001024:Aortic Valve Stenosis / Q000196:embryology / Q000209:etiology* / Q000503:physiopathology; D017209:Apoptosis / Q000502:physiology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D059630:Mesenchymal Stem Cells / Q000502:physiology; D018345:Mice, Knockout; D051881:Receptor, Notch1 / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha
Congenital anomalies of arterial valves; Notch; Tnf; Valvar aortic stenosis