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Blood, 1 March 2007, Vol. 109, No. 5, pp. 1793. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kyriakides, T. R. Search for Related Content PubMed Articles by Kyriakides, T. R. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS Comment on Isenberg et al, page 1945 Thrombospondin says no to NO Themis R. Kyriakides YALE UNIVERSITY Isenberg and colleagues report that thrombospondin-1 (TSP1) acts as an antagonist of nitric oxide (NO)–induced vascular relaxation and limits ischemic tissue survival. This finding identifies a new modulator of vascular contraction and expands the functional repertoire of TSP1. Tissue perfusion, a process that is limited in ischemic conditions, is mediated by the relaxation of vascular smooth muscle cells (VSMCs). This process is regulated by the activation of cGMP-dependent kinase leading to the modulation of intracellular Ca2+ availability and the activity of myosin light chain (MLC) phosphatase. Contraction requires the binding of Ca2+ to calmodulin and the phosphorylation of MLC. These interactions control the association between F-actin–containing stress fibers and the contractile protein myosin leading to contraction. NO, a vasodilatory gas, induces the formation of cGMP leading to VSMC relaxation by promoting actin disassembly. Previously, in vitro studies with VSMCs have shown TSP1 to be an antagonist of NO.1 However, both the mechanism and the biologic relevance of this antagonistic function remained unclear. In this issue of Blood, Isenberg and colleagues expanded on their previous in vitro findings by identifying a mechanism through which TSP1 inhibits the effects of NO on VSMCs. Specifically, the authors demonstrate that TSP1 antagonizes the NO-induced dephosphorylation of MLC, resulting in the prevention of relaxation of contracted VSMCs. Presumably, the effect is mediated by modulation of the cGMP-dependent activation of MLC phosphatase, but this is not confirmed. In addition, Isenberg et al show enhanced NO-mediated increase in skeletal muscle perfusion and myocutaneous flap survival in a model of ischemic injury in TSP1-null mice. Taken together, these observations identify a novel function for TSP1 in the regulation of blood vessel physiology involving its ability to antagonize NO function. As a potent inhibitor of angiogenesis, TSP1 has been shown to be proapoptotic and antiproliferative for endothelial cells and to mediate the adhesive state of vascular cells.2 In addition, TSP1 has been shown to inhibit the activation of proangiogenic enzymes such as matrix metalloproteinases (MMPs).3 Now, the ability of TSP1 to attenuate the effects of NO in VSMCs can be added to the growing list of TSP1 functions. What is the contribution of this mechanism in the development of ischemia? Recently, it was shown that TSP1 expression is highly induced in ischemic muscle and displays perivascular deposition.4 Bone marrow transplant studies suggested a hematopoietic source for TSP1 and implicated a mechanism involving the activation of stroma cell–derived factor-1 by MMP-9. It is also expected that TSP1 would exert its antiangiogenic effect by direct interaction with endothelial cells. Are these, and perhaps other yet-to-be-defined TSP1-specific mechanisms, contributing to the reduced blood flow in ischemic tissues? Studies aimed at the determination of the relative contribution of these mechanisms, perhaps by investigating the participation of specific TSP receptors such as CD36 and CD47, could provide more insight. Footnotes The author declares no competing financial interests. REFERENCES Isenberg JS, Wink DA, Roberts DD. Thrombospondin-1 antagonizes nitric oxide-stimulated vascular smooth muscle cell responses. Cardiovasc Res 2006; 71:785–793.[Abstract/Free Full Text] Adams JC and Lawler J. The thrombospondins. Int J Biochem Cell Biol 2004; 36:961–968.[CrossRef][Medline] [Order article via Infotrieve] Rodriguez-Manzaneque JC, Lane TF, Ortega MA, Hynes RO, Lawler J, Iruela-Arispe ML. Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor. Proc Natl Acad Sci U S A 2001; 98:12485–12490.[Abstract/Free Full Text] Kopp HG, Hooper AT, Broekman MJ, et al. Thrombospondins deployed by thrombopoietic cells determine angiogenic switch and extent of revascularization. J Clin Invest 2006; 116:3277–3291.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Thrombospondin-1 limits ischemic tissue survival by inhibiting nitric oxide–mediated vascular smooth muscle relaxation Jeff S. Isenberg, Fuminori Hyodo, Ken-Ichiro Matsumoto, Martin J. Romeo, Mones Abu-Asab, Maria Tsokos, Periannan Kuppusamy, David A. Wink, Murali C. Krishna, and David D. Roberts Blood 2007 109: 1945-1952. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kyriakides, T. R. Search for Related Content PubMed Articles by Kyriakides, T. R. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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