Thrombospondin-1: a physiological regulator of nitric oxide signaling.
Thrombospondin-1 is a secreted protein that modulates vascular cell behavior via several cell surface receptors. In vitro, nanomolar concentrations of thrombospondin-1 are required to alter endothelial and vascular smooth muscle cell adhesion, proliferation, motility, and survival. Yet, much lower levels of thrombospondin-1 are clearly functional in vivo. This discrepancy was explained with the discovery that the potency of thrombospondin-1 increases more than 100-fold in the presence of physiological levels of nitric oxide (NO). Thrombospondin-1 binding to CD47 inhibits NO signaling by preventing cGMP synthesis and activation of its target cGMP-dependent protein kinase. This potent antagonism of NO signaling allows thrombospondin-1 to acutely constrict blood vessels, accelerate platelet aggregation, and if sustained, inhibit angiogenic responses. Acute antagonism of NO signaling by thrombospondin-1 is important for hemostasis but becomes detrimental for tissue survival of ischemic injuries. New therapeutic approaches targeting thrombospondin-1 or CD47 can improve recovery from ischemic injuries and overcome a deficit in NO-responsiveness in aging. (Part of a Multi-author Review).
Isenberg
J S
JS
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Frazier
W A
WA
Roberts
D D
DD
D000818:Animals; D006801:Humans; D018919:Neovascularization, Physiologic; D009569:Nitric Oxide / Q000378:metabolism*; D015398:Signal Transduction; D019700:Thrombospondin 1 / Q000502:physiology*
D019700:Thrombospondin 1; D009569:Nitric Oxide