Notch activation results in phenotypic and functional changes consistent with endothelial-to-mesenchymal transformation.
Various studies have identified a critical role for Notch signaling in cardiovascular development. In this and other systems, Notch receptors and ligands are expressed in regions that undergo epithelial-to-mesenchymal transformation. However, there is no direct evidence that Notch activation can induce mesenchymal transdifferentiation. In this study we show that Notch activation in endothelial cells results in morphological, phenotypic, and functional changes consistent with mesenchymal transformation. These changes include downregulation of endothelial markers (vascular endothelial [VE]-cadherin, Tie1, Tie2, platelet-endothelial cell adhesion molecule-1, and endothelial NO synthase), upregulation of mesenchymal markers (alpha-smooth muscle actin, fibronectin, and platelet-derived growth factor receptors), and migration toward platelet-derived growth factor-BB. Notch-induced endothelial-to-mesenchymal transformation does not seem to require external regulation and is restricted to cells expressing activated Notch. Jagged1 stimulation of endothelial cells induces a similar mesenchymal transformation, and Jagged1, Notch1, and Notch4 are expressed in the ventricular outflow tract during stages of endocardial cushion formation. This is the first evidence that Jagged1-Notch interactions induce endothelial-to-mesenchymal transformation, and our findings suggest that Notch signaling may be required for proper endocardial cushion differentiation and/or vascular smooth muscle cell development.
Noseda
Michela
M
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
McLean
Graeme
G
Niessen
Kyle
K
Chang
Linda
L
Pollet
Ingrid
I
Montpetit
Rachel
R
Shahidi
Réza
R
Dorovini-Zis
Katerina
K
Li
Linheng
L
Beckstead
Benjamin
B
Durand
Ralph E
RE
Hoodless
Pamela A
PA
Karsan
Aly
A
D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D015703:Antigens, CD; D000077214:Becaplermin; D015820:Cadherins / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation; D002460:Cell Line; D004699:Endocardium / Q000166:cytology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005318:Fetal Heart / Q000378:metabolism* / Q000648:ultrastructure; D018507:Gene Expression Regulation, Developmental; D006346:Heart Septum / Q000196:embryology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D008648:Mesoderm / Q000166:cytology*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D010641:Phenotype; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020574:Proto-Oncogene Proteins c-sis; D051881:Receptor, Notch1; D000074562:Receptor, Notch4; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins / Q000502:physiology; D000072099:Serrate-Jagged Proteins; D012756:Sheep; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors; D014161:Transduction, Genetic; D000099152:Cadherin 5
D000199:Actins; D015703:Antigens, CD; D000077214:Becaplermin; D015820:Cadherins; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D010982:Platelet-Derived Growth Factor; D011506:Proteins; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; D051881:Receptor, Notch1; D000074562:Receptor, Notch4; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; D000072099:Serrate-Jagged Proteins; D014157:Transcription Factors; D000099152:Cadherin 5; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; C497761:NOTCH1 protein, human; C106075:NOTCH4 protein, human; C497762:Notch1 protein, mouse; C073572:Notch4 protein, mouse