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Blood, 1 November 2008, Vol. 112, No. 9, pp. 3533-3534.
Shear activates platelet-derived latent TGF-βUNIVERSITY OF TOKYO
Although platelets are a rich source of latent TGF-β it has not been determined how platelet-derived latent TGF-β is activated in vivo. In this issue of Blood, Ahamed and colleagues report that shear and stirring efficiently activate the latent TGF-β.
LAP is a disulfide-bonded dimer derived from the N-terminal part of the TGF-β precursor, whereas the mature TGF-β is the C-terminal part of the TGF-β precursor. After proteolytic processing from the mature part of TGF-β, LAP remains associated with it by noncovalent interaction, and thereby LAP confers latency to TGF-β. In vitro, latent TGF-β is activated by various treatments which alter the structure of LAPs, including extremely low or high pH, heating at 100°C and treatment by SDS. Under physiological conditions, plasmin and certain proteases activate latent TGF-β through proteolytic digestion of LAP. Thrombospondin-1 (TSP-1) has also been shown to activate latent TGF-β. In this case, TSP-1 interacts with LAP and disrupts the complex between TGF-β and LAPs.2 In addition to LAP and TGF-β, the latent TGF-β complex in human platelets contains a single copy of LTBP,3 which is disulfide-bonded to LAP. Latent TGF-β without LTBP is called the small latent complex (SLC) while that with LTBP is called the large latent complex (LLC). Out of the 4 isoforms of LTBPs, LTBP-1 is the major form in human platelets. As described above, LAP is sufficient to confer latency to TGF-β. But, then what are the functions of LTBP-1? Since LTBP-1 binds to ECM, it may function for proper localization of the latent TGF-β complex in vivo. In addition, recent findings revealed that LTBP-1 plays an important role in activation of latent TGF-β in vivo.
Annes et al4 reported that LLC, not SLC, is activated by a traction-mediated mechanism in vivo. The TGF-β1 (and TGF-β3) LAPs contain a RGD sequence and bind to certain integrins, including
Platelets are known to be a rich source of LLC of TGF-β, which is stored in In this issue of Blood, Ahamed et al report that shear forces or stirring induce activation of platelet-derived latent TGF-β. Without stirring, only 0.2% of TGF-β1 was active, but after stirring for 2 hours at 1200 rpm at 37°C, TGF-β activity increased to approximately 7% of the total (3.5 ± 0.5 ng/mL active TGF-β). Shear forces also activated the latent TGF-β to a similar extent. They also showed that thiol-disulfide exchange contributes to activation of the latent TGF-β. Most importantly, SLC was not activated by stirring, indicating the significant role of LTBP-1 in the stirring-induced activation of the latent TGF-β. Although the molecular mechanism of the stirring-induced activation of TGF-β has not been fully elucidated, it is likely to occur in a manner similar to the traction-mediated activation controlled by interaction of LLC with integrin and ECM. Platelet-derived TGF-β may play an important role in the maintenance of vascular homeostasis as well as in the development of atherosclerosis.7 It arrests bleeding by inhibition of fibrinolysis, and induces deposition of fibrin. During the development of atherosclerosis, TGF-β stimulates tissue fibrosis and inhibits local inflammation. It is also well known to inhibit growth and migration of endothelial cells as well as induce differentiation of mural precursors into pericytes and smooth muscle cells. Shear forces may thus regulate these processes in blood vessels through activation of latent TGF-β.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests.
REFERENCES
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