Published online before print February 26, 2004, doi: 10.1161/01.RES.0000124300.76171.C9
© 2004 American Heart Association, Inc.
Molecular Medicine |
Notch Activation Results in Phenotypic and Functional Changes Consistent With Endothelial-to-Mesenchymal Transformation
From the Department of Pathology and Laboratory Medicine (M.N., I.P., A.K.) and Experimental Medicine Program (G.M., K.N., L.C., A.K.), University of British Columbia; Department of Medical Biophysics (M.N., G.M., K.N., L.C., I.P., R.E.D., A.K.), Terry Fox Research Laboratories (R.M., P.A.H.), and Department of Pathology and Laboratory Medicine (A.K.), British Columbia Cancer Agency; and Department of Pathology (R.S., K.D.-Z.), Division of Neuropathology, University of British Columbia and Vancouver Hospital and Health Sciences Centre, Vancouver, British Columbia, Canada; Stem Cell Research Laboratory (L.L.), Stowers Institute for Medical Research, Kansas City, Mo; and Department of Bioengineering (B.B.), University of Washington, Seattle, Wash.
Correspondence to Aly Karsan, Department of Pathology and Laboratory Medicine and Experimental Medicine Program, University of British Columbia, Vancouver, BC V6T 2B5, Canada. E-mail akarsan{at}bccrc.ca
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 (
-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.
Key Words: endothelial-to-mesenchymal transformation • Notch • Jagged1 • endocardial cushion
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