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The Journal of Immunology, 2006, 176: 12-15.
Copyright © 2006 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Extracellular High Mobility Group Box-1 Protein Is a Proangiogenic Cytokine1

Stefania Mitola2,*, Mirella Belleri2,*, Chiara Urbinati*, Daniela Coltrini{dagger}, Bianca Sparatore{ddagger}, Marco Pedrazzi{ddagger}, Edon Melloni{ddagger} and Marco Presta3,*

* Unit of General Pathology and Immunology and {dagger} Unit of Histology, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy; and {ddagger} Section of Biochemistry, Department of Experimental Medicine, University of Genova, Genova, Italy

The chromosomal high mobility group box-1 (HMGB1) protein acts as a proinflammatory cytokine when released in the extracellular environment by necrotic and inflammatory cells. In the present study, we show that HMGB1 exerts proangiogenic effects by inducing MAPK ERK1/2 activation, cell proliferation, and chemotaxis in endothelial cells of different origin. Accordingly, HMGB1 stimulates membrane ruffling and repair of a mechanically wounded endothelial cell monolayer and causes endothelial cell sprouting in a three-dimensional fibrin gel. In keeping with its in vitro properties, HMGB1 stimulates neovascularization when applied in vivo on the top of the chicken embryo chorioallantoic membrane whose blood vessels express the HMGB1 receptor for advanced glycation end products (RAGE). Accordingly, RAGE blockade by neutralizing Abs inhibits HMGB1-induced neovascularization in vivo and endothelial cell proliferation and membrane ruffling in vitro. Taken together, the data identify HMGB1/RAGE interaction as a potent proangiogenic stimulus.


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