The hypothesis that thrombospondin-1 (TSP-1) can exert opposite effects on angiogenesis depending on the functional status of its domains/fragments was investigated. In the rabbit cornea, TSP-1 inhibited angiogenesis induced by fibroblast growth factor-2 (FGF-2). However, when tested per se, TSP-1 was able to elicit an angiogenic response comparable to that induced by FGF-2. Induction of angiogenesis was dose-dependent (20 ng - 2 μg/pellet), was prevented by anti-TSP antibodies or by heat-inactivation of TSP-1, and was not due to inflammatory mediators, to FGF-2 or to TGF-β. Equimolar concentrations of the 25 kDa heparin binding fragment of TSP-1 were even more efficient than the whole molecule, and promoted the angiogenic activity of FGF-2. On the contrary, the 140 kDa fragment of TSP-1 did not induce angiogenesis and turned off the angiogenic response to FGF-2. The 25 kDa fragment and TSP-1, but not the 140 kDa fragment, increased endothelial cell invasiveness and stimulated the production and activation of matrix metalloproteinase-2 (MMP-2). Moreover, the 25 kDa fragment reduced the synthesis of the MMP-2 inhibitor TIMP-2, while the 140 kDa fragment caused a twofold increase in TIMP-2 production and inhibited MMPs stimulation by TSP-1 and FGF-2. We conclude that TSP-1 is a source of smaller mediators of angiogenesis, which affect in an opposite way endothelial cell functions and proteolytic activity, thus resulting in an opposite final effect on angiogenesis.
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|Titolo:||The heparin binding 25kDa fragment of thrombospondin-1 promotes angiogenesis and modulates gelatinases and TIMP-2 in endothelial cells|
|Citazione:||G., T., Morbidelli, L., Donnini, S., A., P., H. J., G., R., G., et al. (2000). The heparin binding 25kDa fragment of thrombospondin-1 promotes angiogenesis and modulates gelatinases and TIMP-2 in endothelial cells. THE FASEB JOURNAL, 14(12), 1674-1676.|
|Appare nelle tipologie:||1.1 Articolo in rivista|