Opposing actions of Notch1 and VEGF in post-natal cardiac valve endothelial cells.
The endothelium of the cardiac valves is unique compared the rest of the vasculature in its ability to undergo an endothelial-to-mesenchymal transformation (EMT) in vitro in response to transforming growth factor-beta (TGF-beta). EMT is a critical event during embryonic valve development, and both VEGF-A and Notch1 have been shown to function in this process. Here we investigate the effects of VEGF-A and Notch1 on EMT in clonal endothelial cell (EC) populations isolated from adult aortic valve leaflets. VEGF-A inhibited TGF-beta-induced EMT. Endothelial growth, however, was not affected by VEGF-A or TGF-beta. A positive role for Notch1 was revealed in three experiments: (1) TGF-beta induced Notch1 mRNA in valve ECs, (2) a gamma-secretase inhibitor of Notch1 signaling blocked EMT, and (3) overexpression of a ligand-independent form of Notch1 induced EMT. These results demonstrate, for the first time, that VEGF-A and Notch1 play opposing roles in regulating EMT in post-natal valve endothelium.
Yang
Jeong-Hee
JH
Vascular Biology Program, Department of Surgery, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA.
Wylie-Sears
Jill
J
Bischoff
Joyce
J
D000818:Animals; D001021:Aortic Valve / Q000166:cytology / Q000187:drug effects / Q000254:growth & development*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D006801:Humans; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects / Q000254:growth & development*; D051881:Receptor, Notch1 / Q000502:physiology*; D012756:Sheep; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology
D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D051881:Receptor, Notch1; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2