title: Endothelial nitric oxide signaling regulates Notch1 in aortic valve disease.
abstract: The mature aortic valve is composed of a structured trilaminar extracellular matrix that is interspersed with aortic valve interstitial cells (AVICs) and covered by endothelium. Dysfunction of the valvular endothelium initiates calcification of neighboring AVICs leading to calcific aortic valve disease (CAVD). The molecular mechanism by which endothelial cells communicate with AVICs and cause disease is not well understood. Using a co-culture assay, we show that endothelial cells secrete a signal to inhibit calcification of AVICs. Gain or loss of nitric oxide (NO) prevents or accelerates calcification of AVICs, respectively, suggesting that the endothelial cell-derived signal is NO. Overexpression of Notch1, which is genetically linked to human CAVD, retards the calcification of AVICs that occurs with NO inhibition. In AVICs, NO regulates the expression of Hey1, a downstream target of Notch1, and alters nuclear localization of Notch1 intracellular domain. Finally, Notch1 and NOS3 (endothelial NO synthase) display an in vivo genetic interaction critical for proper valve morphogenesis and the development of aortic valve disease. Our data suggests that endothelial cell-derived NO is a regulator of Notch1 signaling in AVICs in the development of the aortic valve and adult aortic valve disease.
authors.affiliation: Center for Cardiovascular and Pulmonary Research at Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Bosse
authors.forename: Chetan P
authors.initials: CP
authors.lastname: Hans
authors.forename: Ning
authors.initials: N
authors.lastname: Zhao
authors.forename: Sara N
authors.initials: SN
authors.lastname: Koenig
authors.forename: Nianyuan
authors.initials: N
authors.lastname: Huang
authors.forename: Anuradha
authors.initials: A
authors.lastname: Guggilam
authors.forename: Stephanie
authors.initials: S
authors.lastname: LaHaye
authors.forename: Ge
authors.initials: G
authors.lastname: Tao
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Lucchesi
authors.forename: Joy
authors.initials: J
authors.lastname: Lincoln
authors.forename: Brenda
authors.initials: B
authors.lastname: Lilly
authors.forename: Vidu
authors.initials: V
authors.lastname: Garg
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000818:Animals; D001021:Aortic Valve / Q000378:metabolism* / Q000473:pathology; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics; D000082882:Bicuspid Aortic Valve Disease; D002114:Calcinosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006330:Heart Defects, Congenital / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006349:Heart Valve Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D013552:Swine
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D009569:Nitric Oxide; D051881:Receptor, Notch1; D012097:Repressor Proteins; C485631:HEY1 protein, human; C485778:Hey2 protein, mouse; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse