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Prepublished online as a Blood First Edition Paper on July 10, 2003; DOI 10.1182/blood-2003-02-0378.
Submitted February 5, 2003
Accepted June 25, 2003
Generation and role of angiostatin in human platelets
Paul Jurasz, David Alonso, Susana Castro-Blanco, Ferid Murad, and Marek W Radomski*
Department of Pharmacology, University of Alberta, Edmonton, AB, Canada; Department of Integrative Biology and Pharmacology, University of Texas-Houston, Houston, TX, USA
Department of Neuroanatomy and Cell Biology, Cajal Institute, Madrid, Spain
* Corresponding author; email: Marek.Radomski{at}uth.tmc.edu.
Platelets regulate new blood vessel growth, as they contain a number of angiogenesis promoters and inhibitors. Additionally, platelets contain matrix metalloproteinases (MMPs), that when released mediate platelet adhesion and aggregation, and plasminogen a fibrinolytic system enzyme which serves to limit blood clot formation. Enzymatic cleavage of plasminogen by MMPs generates angiostatin, an angiogenesis inhibitor. Therefore, we examined whether platelets generate angiostatin during aggregation in vitro. Platelets were isolated from healthy human donors, and then aggregated with collagen, thrombin, or HT-1080 fibrosarcoma cells. Angiostatin was detected by Western blot analysis in the platelet releasates of all blood donors irrespective of the aggregating agent used. Platelet pellet homogenates showed the presence of angiostatin in all donors, which was released upon aggregation. Furthermore, platelet-derived angiostatin was isolated and purified by lysine-sepharose affinity chromatography from collagen-aggregated platelet releasates. Bioassay of platelet-derived angiostatin showed that it inhibited the formation of capillary structures by human umbilical vein endothelial cells (HUV-EV-C) in an in vitro angiogenesis model. Inhibition of angiostatin in platelet releasates promoted the formation of capillary structures by HUV-EV-C. We conclude that healthy human platelets contain angiostatin which is released in active form during platelet aggregation, and platelet-derived angiostatin has the capacity to inhibit angiogenesis.
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