Thrombospondin-1 limits ischemic tissue survival by inhibiting nitric oxide-mediated vascular smooth muscle relaxation.
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.
Isenberg
Jeff S
JS
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1500, USA.
Hyodo
Fuminori
F
Matsumoto
Ken-Ichiro
K
Romeo
Martin J
MJ
Abu-Asab
Mones
M
Tsokos
Maria
M
Kuppusamy
Periannan
P
Wink
David A
DA
Krishna
Murali C
MC
Roberts
David D
DD
D000199:Actins / Q000378:metabolism; D000818:Animals; D024722:Cardiac Myosins / Q000378:metabolism; D007511:Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D051379:Mice; D008810:Mice, Inbred C57BL; D009126:Muscle Relaxation / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology*; D018994:Myosin Light Chains / Q000378:metabolism; D009336:Necrosis / Q000201:enzymology / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010766:Phosphorylation; D019700:Thrombospondin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D000199:Actins; D018994:Myosin Light Chains; D019700:Thrombospondin 1; C107184:myosin light chain 2; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D024722:Cardiac Myosins; D010100:Oxygen