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 journalArticle

    78 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

    Fingerprint

    Thrombospondin 1
    Tissue Survival
    Muscle Relaxation
    Vascular Smooth Muscle
    Muscle
    Nitric Oxide
    Tissue
    Smooth Muscle Myocytes
    Cells
    Perfusion
    Myosin Light Chains
    Myocutaneous Flap
    Oximetry
    Electron Spin Resonance Spectroscopy
    Phosphorylation
    Vasodilation
    Blood Vessels
    Actins
    Skeletal Muscle
    Collagen

    All Science Journal Classification (ASJC) codes

    • Biochemistry
    • Immunology
    • Hematology
    • Cell Biology

    Cite this

    Isenberg, J. S., Hyodo, F., Matsumoto, K. I., Romeo, M. J., Abu-Asab, M., Tsokos, M., ... Roberts, D. D. (2007). Thrombospondin-1 limits ischemic tissue survival by inhibiting nitric oxide-mediated vascular smooth muscle relaxation. Blood, 109(5), 1945-1952. https://doi.org/10.1182/blood-2006-08-041368

    Thrombospondin-1 limits ischemic tissue survival by inhibiting nitric oxide-mediated vascular smooth muscle relaxation. / Isenberg, Jeff S.; Hyodo, Fuminori; Matsumoto, Ken Ichiro; Romeo, Martin J.; Abu-Asab, Mones; Tsokos, Maria; Kuppusamy, Periannan; Wink, David A.; Krishna, Murali C.; Roberts, David D.

    In: Blood, Vol. 109, No. 5, 01.03.2007, p. 1945-1952.

    Research output: Contribution to journalArticle

    Isenberg, JS, Hyodo, F, Matsumoto, KI, Romeo, MJ, Abu-Asab, M, Tsokos, M, Kuppusamy, P, Wink, DA, Krishna, MC & Roberts, DD 2007, 'Thrombospondin-1 limits ischemic tissue survival by inhibiting nitric oxide-mediated vascular smooth muscle relaxation', Blood, vol. 109, no. 5, pp. 1945-1952. https://doi.org/10.1182/blood-2006-08-041368
    Isenberg, Jeff S. ; Hyodo, Fuminori ; Matsumoto, Ken Ichiro ; Romeo, Martin J. ; Abu-Asab, Mones ; Tsokos, Maria ; Kuppusamy, Periannan ; Wink, David A. ; Krishna, Murali C. ; Roberts, David D. / Thrombospondin-1 limits ischemic tissue survival by inhibiting nitric oxide-mediated vascular smooth muscle relaxation. In: Blood. 2007 ; Vol. 109, No. 5. pp. 1945-1952.
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