Copyright © 2006, European Society of Cardiology
Thrombospondin-1 antagonizes nitric oxide-stimulated vascular smooth muscle cell responses
aLaboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States
bRadiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States
* Corresponding author. NIH, Building 10, Room 2A33, 10 Center Drive MSC1500, Bethesda, MD 20892-1500, United States. Tel.: +1 301 496 6264. Email address: droberts{at}helix.nih.gov
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.
KEYWORDS Smooth muscle; Signal transduction; Nitric oxide; Extracellular matrix
Time for primary review 19 days
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