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Published online April 30, 2007
doi:10.1083/jcb.200610086
The Journal of Cell Biology, Vol. 177, No. 3, 539-549
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Fuster et al.
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Article

 Genetic alteration of endothelial heparan sulfate selectively inhibits tumor angiogenesis

Mark M. Fuster1, Lianchun Wang2, Janice Castagnola2, Lyudmila Sikora4, Krisanavane Reddi1, Phillip H.A. Lee3,5, Katherine A. Radek3,5, Manuela Schuksz2, Joseph R. Bishop2, Richard L. Gallo3,5, P. Sriramarao4, and Jeffrey D. Esko2

1 Department of Medicine, Division of Pulmonary and Critical Care Medicine, 2 Department of Cellular and Molecular Medicine, and 3 Division of Dermatology, University of California, San Diego, La Jolla, CA 92093
4 Division of Vascular Biology, La Jolla Institute for Molecular Medicine, San Diego, CA 92121
5 Veterans Affairs Medical Center, San Diego, CA 92161

Correspondence to Jeffrey D. Esko: jesko{at}ucsd.edu

To examine the role of endothelial heparan sulfate during angiogenesis, we generated mice bearing an endothelial-targeted deletion in the biosynthetic enzyme N-acetylglucosamine N-deacetylase/N-sulfotransferase 1 (Ndst1). Physiological angiogenesis during cutaneous wound repair was unaffected, as was growth and reproductive capacity of the mice. In contrast, pathological angiogenesis in experimental tumors was altered, resulting in smaller tumors and reduced microvascular density and branching. To simulate the angiogenic environment of the tumor, endothelial cells were isolated and propagated in vitro with proangiogenic growth factors. Binding of FGF-2 and VEGF164 to cells and to purified heparan sulfate was dramatically reduced. Mutant endothelial cells also exhibited altered sprouting responses to FGF-2 and VEGF164, reduced Erk phosphorylation, and an increase in apoptosis in branching assays. Corresponding changes in growth factor binding to tumor endothelium and apoptosis were also observed in vivo. These findings demonstrate a cell-autonomous effect of heparan sulfate on endothelial cell growth in the context of tumor angiogenesis.

Abbreviations used in this paper: LLC, Lewis lung carcinoma; Ndst, N-deacetylase/N-sulfotransferase.


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