Thrombospondin-1 modulates angiogenesis in vitro by up-regulation of matrix metalloproteinase-9 in endothelial cells.
Evidence suggests that thrombospondin-1 (TSP-1), a 450-kDa glycoprotein in platelets and extracellular matrix, is involved in angiogenesis. However, the mechanisms by which TSP-1 regulates angiogenesis are unknown, and the exact role of TSP-1 in angiogenesis has been controversial: both stimulatory and inhibitory effects of TSP-1 have been reported. In this study, we evaluated the effect of TSP-1 on the capacity of bovine aortic endothelial (BAE) cells to both invade and form microvessel-like tubes in collagen gels. BAE cell tube formation was enhanced by exogenous TSP-1 at relatively low concentrations (1-10 microg/ml) but inhibited at higher concentrations of TSP-1 (>15 microg/ml). In addition, we correlated this biphasic effect on tube formation with the capacity of TSP-1 to stimulate the activity of a matrix metalloproteinase-9 (MMP-9) in BAE cell collagen gel cultures. The TSP-1-mediated stimulation of MMP-9 activity was specific and dose- and time-dependent. Furthermore, TSP-1-stimulated BAE cell invasion and tube formation were reversed by antibodies against both TSP-1 and MMP-9, suggesting that TSP-1 modulates endothelial cell invasion and morphogenesis in vitro by a mechanism involving the regulation of MMP-9 activity. These findings support the conclusion that TSP-1 is a multifunctional modulator of angiogenesis and are consistent with the dynamic presence of TSP-1 in remodeling tissues in which matrix degradation is required.
Qian
X
X
Department of Surgery, MCP-Hahnemann School of Medicine, Allegheny University of the Health Sciences, Philadelphia, Pennsylvania 19102, USA.
Wang
T N
TN
Rothman
V L
VL
Nicosia
R F
RF
Tuszynski
G P
GP
D000818:Animals; D002417:Cattle; D002455:Cell Division; D002465:Cell Movement; D002478:Cells, Cultured; D003094:Collagen; D017364:Collagenases / Q000096:biosynthesis / Q000378:metabolism*; D017077:Culture Media, Conditioned; D004730:Endothelium, Vascular / Q000166:cytology* / Q000201:enzymology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005353:Fibronectins; D018093:Gelatinases / Q000032:analysis; D005782:Gels; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D010618:Phenanthrolines / Q000494:pharmacology; D010662:Phenylmercuric Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D019699:Thrombospondins; D015854:Up-Regulation
D017077:Culture Media, Conditioned; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D005782:Gels; D061965:Matrix Metalloproteinase Inhibitors; D008562:Membrane Glycoproteins; D009842:Oligopeptides; D010618:Phenanthrolines; D011480:Protease Inhibitors; D019699:Thrombospondins; C010024:4-aminophenylmercuriacetate; D003094:Collagen; D017364:Collagenases; D018093:Gelatinases; D020780:Matrix Metalloproteinase 9; D010662:Phenylmercuric Acetate; C025205:1,10-phenanthroline