This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Leong, K. G. Articles by Karsan, A. Search for Related Content PubMed PubMed Citation Articles by Leong, K. G. Articles by Karsan, A.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, April 2002, p. 2830-2841, Vol. 22, No. 8
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.8.2830-2841.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Activated Notch4 Inhibits Angiogenesis: Role of ß1-Integrin Activation

Departments of Experimental Medicine,¹ Pathology and Laboratory Medicine, University of British Columbia and British Columbia Cancer Agency,³ Department of Medical Biophysics, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada,² Stem Cell Research Laboratory, Stowers Institute for Medical Research, Kansas City, Missouri 64110,⁴ Institute for Systems Biology, Seattle, Washington 98105⁵

Received 22 May 2001/ Returned for modification 7 July 2001/ Accepted 9 January 2002

Notch4 is a member of the Notch family of transmembrane receptors that is expressed primarily on endothelial cells. Activation of Notch in various cell systems has been shown to regulate cell fate decisions. The sprouting of endothelial cells from microvessels, or angiogenesis, involves the modulation of the endothelial cell phenotype. Based on the function of other Notch family members and the expression pattern of Notch4, we postulated that Notch4 activation would modulate angiogenesis. Using an in vitro endothelial-sprouting assay, we show that expression of constitutively active Notch4 in human dermal microvascular endothelial cells (HMEC-1) inhibits endothelial sprouting. We also show that activated Notch4 inhibits vascular endothelial growth factor (VEGF)-induced angiogenesis in the chick chorioallantoic membrane in vivo. Activated Notch4 does not inhibit HMEC-1 proliferation or migration through fibrinogen. However, migration through collagen is inhibited. Our data show that Notch4 cells exhibit increased ß1-integrin-mediated adhesion to collagen. HMEC-1 expressing activated Notch4 do not have increased surface expression of ß1-integrins. Rather, we demonstrate that Notch4-expressing cells display ß1-integrin in an active, high-affinity conformation. Furthermore, using function-activating ß1-integrin antibodies, we demonstrate that activation of ß1-integrins is sufficient to inhibit VEGF-induced endothelial sprouting in vitro and angiogenesis in vivo. Our findings suggest that constitutive Notch4 activation in endothelial cells inhibits angiogenesis in part by promoting ß1-integrin-mediated adhesion to the underlying matrix.

This article has been cited by other articles:

• Dou, G.-R., Wang, Y.-C., Hu, X.-B., Hou, L.-H., Wang, C.-M., Xu, J.-F., Wang, Y.-S., Liang, Y.-M., Yao, L.-B., Yang, A.-G., Han, H. (2008). RBP-J, the transcription factor downstream of Notch receptors, is essential for the maintenance of vascular homeostasis in adult mice. FASEB J. 22: 1606-1617 [Abstract] [Full Text]  
• Karsan, A. (2008). Notch and Integrin Affinity: A Sticky Situation. Sci Signal 1: pe2-pe2 [Abstract] [Full Text]  
• Leong, K. G., Niessen, K., Kulic, I., Raouf, A., Eaves, C., Pollet, I., Karsan, A. (2007). Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin. J. Exp. Med. 204: 2935-2948 [Abstract] [Full Text]  
• Zhande, R., Dauphinee, S. M., Thomas, J. A., Yamamoto, M., Akira, S., Karsan, A. (2007). FADD Negatively Regulates Lipopolysaccharide Signaling by Impairing Interleukin-1 Receptor-Associated Kinase 1-MyD88 Interaction. Mol. Cell. Biol. 27: 7394-7404 [Abstract] [Full Text]  
• Roca, C., Adams, R. H. (2007). Regulation of vascular morphogenesis by Notch signaling. Genes Dev. 21: 2511-2524 [Abstract] [Full Text]  
• Hodkinson, P. S., Elliott, Paul. A., Lad, Y., McHugh, B. J., MacKinnon, A. C., Haslett, C., Sethi, T. (2007). Mammalian NOTCH-1 Activates beta1 Integrins via the Small GTPase R-Ras. J. Biol. Chem. 282: 28991-29001 [Abstract] [Full Text]  
• Morrow, D., Cullen, J. P., Cahill, P. A., Redmond, E. M. (2007). Cyclic Strain Regulates the Notch/CBF-1 Signaling Pathway in Endothelial Cells: Role in Angiogenic Activity. Arterioscler. Thromb. Vasc. Bio. 27: 1289-1296 [Abstract] [Full Text]  
• Wu, J., Bresnick, E. H. (2007). Glucocorticoid and Growth Factor Synergism Requirement for Notch4 Chromatin Domain Activation. Mol. Cell. Biol. 27: 2411-2422 [Abstract] [Full Text]  
• Leslie, J. D., Ariza-McNaughton, L., Bermange, A. L., McAdow, R., Johnson, S. L., Lewis, J. (2007). Endothelial signalling by the Notch ligand Delta-like 4 restricts angiogenesis. Development 134: 839-844 [Abstract] [Full Text]  
• Murphy, S., Larrivee, B., Pollet, I., Craig, K. S., Williams, D. E., Huang, X.-H., Abbott, M., Wong, F., Curtis, C., Conrads, T. P., Veenstra, T., Puri, M., Hsiang, Y., Roberge, M., Andersen, R. J., Karsan, A. (2006). Identification of Sokotrasterol Sulfate As a Novel Proangiogenic Steroid. Circ. Res. 99: 257-265 [Abstract] [Full Text]  
• Leong, K. G., Karsan, A. (2006). Recent insights into the role of Notch signaling in tumorigenesis. Blood 107: 2223-2233 [Abstract] [Full Text]  
• Campos, L. S., Decker, L., Taylor, V., Skarnes, W. (2006). Notch, Epidermal Growth Factor Receptor, and beta1-Integrin Pathways Are Coordinated in Neural Stem Cells. J. Biol. Chem. 281: 5300-5309 [Abstract] [Full Text]  
• Williams, C. K., Li, J.-L., Murga, M., Harris, A. L., Tosato, G. (2006). Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function. Blood 107: 931-939 [Abstract] [Full Text]  
• Patel, N. S., Li, J.-L., Generali, D., Poulsom, R., Cranston, D. W., Harris, A. L. (2005). Up-regulation of Delta-like 4 Ligand in Human Tumor Vasculature and the Role of Basal Expression in Endothelial Cell Function. Cancer Res. 65: 8690-8697 [Abstract] [Full Text]  
• Larrivee, B., Niessen, K., Pollet, I., Corbel, S. Y., Long, M., Rossi, F. M., Olive, P. L., Karsan, A. (2005). Minimal Contribution of Marrow-Derived Endothelial Precursors to Tumor Vasculature. J. Immunol. 175: 2890-2899 [Abstract] [Full Text]  
• Noseda, M., Niessen, K., McLean, G., Chang, L., Karsan, A. (2005). Notch-Dependent Cell Cycle Arrest Is Associated With Downregulation of Minichromosome Maintenance Proteins. Circ. Res. 97: 102-104 [Abstract] [Full Text]  
• Limbourg, F. P., Takeshita, K., Radtke, F., Bronson, R. T., Chin, M. T., Liao, J. K. (2005). Essential Role of Endothelial Notch1 in Angiogenesis. Circulation 111: 1826-1832 [Abstract] [Full Text]  
• Wu, J., Iwata, F., Grass, J. A., Osborne, C. S., Elnitski, L., Fraser, P., Ohneda, O., Yamamoto, M., Bresnick, E. H. (2005). Molecular Determinants of NOTCH4 Transcription in Vascular Endothelium. Mol. Cell. Biol. 25: 1458-1474 [Abstract] [Full Text]  
• Noseda, M., Chang, L., McLean, G., Grim, J. E., Clurman, B. E., Smith, L. L., Karsan, A. (2004). Notch Activation Induces Endothelial Cell Cycle Arrest and Participates in Contact Inhibition: Role of p21Cip1 Repression. Mol. Cell. Biol. 24: 8813-8822 [Abstract] [Full Text]  
• Vercauteren, S. M., Sutherland, H. J. (2004). Constitutively active Notch4 promotes early human hematopoietic progenitor cell maintenance while inhibiting differentiation and causes lymphoid abnormalities in vivo. Blood 104: 2315-2322 [Abstract] [Full Text]  
• MacKenzie, F., Duriez, P., Larrivee, B., Chang, L., Pollet, I., Wong, F., Yip, C., Karsan, A. (2004). Notch4-induced inhibition of endothelial sprouting requires the ankyrin repeats and involves signaling through RBP-J{kappa}. Blood 104: 1760-1768 [Abstract] [Full Text]  
• Das, I., Craig, C., Funahashi, Y., Jung, K.-M., Kim, T.-W., Byers, R., Weng, A. P., Kutok, J. L., Aster, J. C., Kitajewski, J. (2004). Notch Oncoproteins Depend on {gamma}-Secretase/Presenilin Activity for Processing and Function. J. Biol. Chem. 279: 30771-30780 [Abstract] [Full Text]  
• Dixelius, J., Jakobsson, L., Genersch, E., Bohman, S., Ekblom, P., Claesson-Welsh, L. (2004). Laminin-1 Promotes Angiogenesis in Synergy with Fibroblast Growth Factor by Distinct Regulation of the Gene and Protein Expression Profile in Endothelial Cells. J. Biol. Chem. 279: 23766-23772 [Abstract] [Full Text]  
• Morikawa, Y., Cserjesi, P. (2004). Extra-embryonic vasculature development is regulated by the transcription factor HAND1. Development 131: 2195-2204 [Abstract] [Full Text]  
• Noseda, M., McLean, G., Niessen, K., Chang, L., Pollet, I., Montpetit, R., Shahidi, R., Dorovini-Zis, K., Li, L., Beckstead, B., Durand, R. E., Hoodless, P. A., Karsan, A. (2004). Notch Activation Results in Phenotypic and Functional Changes Consistent With Endothelial-to-Mesenchymal Transformation. Circ. Res. 94: 910-917 [Abstract] [Full Text]  
• MacKenzie, F., Duriez, P., Wong, F., Noseda, M., Karsan, A. (2004). Notch4 Inhibits Endothelial Apoptosis via RBP-J{kappa}-dependent and -independent Pathways. J. Biol. Chem. 279: 11657-11663 [Abstract] [Full Text]  
• Whitehead, K. J., Plummer, N. W., Adams, J. A., Marchuk, D. A., Li, D. Y. (2004). Ccm1 is required for arterial morphogenesis: implications for the etiology of human cavernous malformations. Development 131: 1437-1448 [Abstract] [Full Text]  
• Favre, C. J., Mancuso, M., Maas, K., McLean, J. W., Baluk, P., McDonald, D. M. (2003). Expression of genes involved in vascular development and angiogenesis in endothelial cells of adult lung. Am. J. Physiol. Heart Circ. Physiol. 285: H1917-H1938 [Abstract] [Full Text]  
• Orecchia, A., Lacal, P. M., Schietroma, C., Morea, V., Zambruno, G., Failla, C. M. (2003). Vascular endothelial growth factor receptor-1 is deposited in the extracellular matrix by endothelial cells and is a ligand for the {alpha}5{beta}1 integrin. J. Cell Sci. 116: 3479-3489 [Abstract] [Full Text]  
• Pollet, I., Opina, C. J., Zimmerman, C., Leong, K. G., Wong, F., Karsan, A. (2003). Bacterial lipopolysaccharide directly induces angiogenesis through TRAF6-mediated activation of NF-{kappa}B and c-Jun N-terminal kinase. Blood 102: 1740-1742 [Abstract] [Full Text]  
• Horiuchi, K., Weskamp, G., Lum, L., Hammes, H.-P., Cai, H., Brodie, T. A., Ludwig, T., Chiusaroli, R., Baron, R., Preissner, K. T., Manova, K., Blobel, C. P. (2003). Potential Role for ADAM15 in Pathological Neovascularization in Mice. Mol. Cell. Biol. 23: 5614-5624 [Abstract] [Full Text]  
• Iso, T., Hamamori, Y., Kedes, L. (2003). Notch Signaling in Vascular Development. Arterioscler. Thromb. Vasc. Bio. 23: 543-553 [Abstract] [Full Text]