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, David D. Roberts

    Research output: Contribution to journalArticlepeer-review

    86 Citations (Scopus)

    Abstract

    The nitric oxide (NO)/cGMP pathway, by relaxing vascular smooth muscle cells, is a major physiologic regulator of tissue perfusion. We now identify thrombospondin-1 as a potent antagonist of NO for regulating F-actin assembly and myosin light chain phosphorylation in vascular smooth muscle cells. Thrombospondin-1 prevents NO-mediated relaxation of precontracted vascular smooth muscle cells in a collagen matrix. Functional magnetic resonance imaging demonstrated that an NO-mediated increase in skeletal muscle perfusion was enhanced in thrombospondin-1-null relative to wild-type mice, implicating endogenous thrombospondin-1 as a physiologic antagonist of NO-mediated vasodilation. Using a random myocutaneous flap model for ischemic injury, tissue survival was significantly enhanced in thrombospondin-1-null mice. Improved flap survival correlated with increased recovery of oxygen levels in the ischemic tissue of thrombospondin-1-null mice as measured by electron paramagnetic resonance oximetry. These findings demonstrate an important antagonistic relation between NO/cGMP signaling and thrombospondin-1 in vascular smooth muscle cells to regulate vascular tone and tissue perfusion.

    Original languageEnglish
    Pages (from-to)1945-1952
    Number of pages8
    JournalBlood
    Volume109
    Issue number5
    DOIs
    Publication statusPublished - Mar 1 2007

    All Science Journal Classification (ASJC) codes

    • Biochemistry
    • Immunology
    • Hematology
    • Cell Biology

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