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Antiangiogenic Effects of Latent Antithrombin through Perturbed Cell-Matrix Interactions and Apoptosis of Endothelial Cells¹

Department of Genetics and Pathology, Rudbeck Laboratory, S-751 85 Uppsala [H. L., J. D., L. C-W.]; The Ludwig Institute for Cancer Research, Biomedical Center, S-751 24 Uppsala [T. S., A. Ö.]; and Department of Veterinary Medical Chemistry, Swedish University of Agricultural Sciences, Biomedical Center, S-751 23 Uppsala [K. Y., I. B.], Sweden

Antithrombin is a plasma protein of the serpin superfamily that may occur as several conformational variants. The native form of antithrombin is a major regulator of blood clotting. In the present study, we have identified the mechanism underlying the antiangiogenic action of a heat-denatured form, denoted latent antithrombin. Fibroblast growth factor (FGF)-induced angiogenesis in the chick embryo and angiogenesis in mouse fibrosarcoma tumors were inhibited by treatment with latent antithrombin at 1 mg/kg/day. Thermolysin-cleaved and native antithrombin were less efficient in these respects. Treatment with latent antithrombin induced apoptosis of cultured endothelial cells and inhibited cell migration toward FGF-2. Under these conditions, FGF-2-stimulated FGF receptor kinase activity was unaffected. However, actin reorganization, activation of focal adhesion kinase, and focal adhesion formation were disturbed by latent antithrombin treatment of FGF-2-stimulated endothelial cells. These data indicate that latent antithrombin induces apoptosis of endothelial cells by disrupting cell-matrix interactions through uncoupling of focal adhesion kinase.

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