Thrombospondin-1 limits ischemic tissue survival by inhibiting nitric oxide–mediated vascular smooth muscle relaxation
Open Access
- 2 November 2006
- journal article
- Published by American Society of Hematology in Blood
- Vol. 109 (5), 1945-1952
- https://doi.org/10.1182/blood-2006-08-041368
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 antag-onistic relation between NO/cGMP signaling and thrombospondin-1 in vascular smooth muscle cells to regulate vascular tone and tissue perfusion.Keywords
This publication has 50 references indexed in Scilit:
- Absolute oxygen tension (pO2) in murine fatty and muscle tissue as determined by EPRMagnetic Resonance in Medicine, 2005
- Role of Nitric Oxide in Surgical Flap SurvivalJournal of the American College of Surgeons, 2005
- Endogenous thrombospondin-1 is not necessary for proliferation but is permissive for vascular smooth muscle cell responses to platelet-derived growth factorMatrix Biology, 2005
- ABT-510Drugs of the Future, 2005
- Functional regulation of T lymphocytes by modulatory extracellular matrix proteinsThe International Journal of Biochemistry & Cell Biology, 2004
- Thrombospondin‐1 as an endogenous inhibitor of angiogenesis and tumor growthJournal of Cellular and Molecular Medicine, 2002
- Sulfatide Protects Rat Skin Flaps against Ischemia–Reperfusion InjuryJournal of Surgical Research, 1998
- Secondary ischemic tolerance improved by administration of L-NAME in rat flapsMicrosurgery, 1996
- Free Tissue Failure Is Not an All-or-None PhenomenonPlastic and Reconstructive Surgery, 1995
- The Dorsal Skin-Flap Model in the RatPlastic and Reconstructive Surgery, 1993