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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

Kevin G. Leong,1,2 Xiaolong Hu,3 Linheng Li,4 Michela Noseda,2,3 Bruno Larrivée,1,2 Christopher Hull,2,3 Leroy Hood,5 Fred Wong,2,3 and Aly Karsan1,2,3*

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.

* Corresponding author. Mailing address: Department of Medical Biophysics, British Columbia Cancer Research Centre, 601 West 10th Ave., Vancouver, British Columbia, Canada V5Z 1L3. Phone: (604) 877-6248. Fax: (604) 877-6002. E-mail: akarsan{at}bccancer.bc.ca.

Molecular and Cellular Biology, April 2002, p. 2830-2841, Vol. 22, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.8.2830-2841.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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