Thrombospondin-1 antagonizes nitric oxide-stimulated vascular smooth muscle cell responses.
OBJECTIVE
Endothelial-derived nitric oxide (NO), by increasing cGMP, is a major physiological regulator of vascular tone and of vascular smooth muscle cell (VSMC) adhesion, chemotaxis, and proliferation. Thrombospondin-1 is a potent antagonist of NO/cGMP signaling in endothelial cells. Because endothelial and VSMC typically exhibit opposing responses to thrombospondin-1, we examined thrombospondin-1 effects on NO signaling in VSMC.


METHODS
Effects of exogenous thrombospondin-1 on human VSMC adhesion, chemotaxis, proliferation, and cGMP signaling were examined. Endogenous thrombospondin-1 function was characterized by comparing NO signaling in VSMC from wild type and thrombospondin-1 null mice.


RESULTS
Picomolar concentrations of exogenous thrombospondin-1 prevented adhesive, chemotactic, and proliferative responses of human aortic VSMC stimulated by low dose NO. A recombinant CD36-binding domain of thrombospondin-1 or antibody ligation of CD36 similarly inhibited NO-stimulated VSMC responses. Thrombospondin-1 and CD36 ligation inhibited NO responses in VSMC by preventing cGMP accumulation. Thrombospondin-1 null VSMC responses to NO and cGMP signaling were enhanced relative to wild type murine VSMC.


CONCLUSIONS
In the presence of NO, thrombospondin-1 is converted from a weak stimulator to a potent inhibitor of VSMC responses. Both exogenous and endogenous thrombospondin-1 inhibit NO signaling in VSMC. This activity is mediated by the type 1 repeats and utilizes the same CD36-dependent cGMP signaling pathway in endothelial and VSMC.
Isenberg
Jeff S
JS
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Wink
David A
DA
Roberts
David D
DD
D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D003864:Depression, Chemical; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D019700:Thrombospondin 1 / Q000235:genetics / Q000494:pharmacology*
D018955:CD36 Antigens; D019700:Thrombospondin 1; D009569:Nitric Oxide; D006152:Cyclic GMP