Antiangiogenic effects of latent antithrombin through perturbed cell-matrix interactions and apoptosis of endothelial cells.
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.
Larsson
H
H
Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala, Sweden.
Sjöblom
T
T
Dixelius
J
J
Ostman
A
A
Ylinenjärvi
K
K
Björk
I
I
Claesson-Welsh
L
L
D000482:Allantois / Q000098:blood supply / Q000187:drug effects; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000991:Antithrombins / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002450:Cell Communication / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply / Q000187:drug effects; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D005109:Extracellular Matrix / Q000187:drug effects; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors; D005354:Fibrosarcoma / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D008222:Lymphokines / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D000991:Antithrombins; D016228:Endothelial Growth Factors; D008222:Lymphokines; D017468:Receptors, Fibroblast Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; C496349:Fgfr1 protein, mouse; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse