Thrombospondins: from structure to therapeutics
- 12 January 2008
- journal article
- review article
- Published by Springer Science and Business Media LLC in Cellular and Molecular Life Sciences
- Vol. 65 (5), 728-742
- https://doi.org/10.1007/s00018-007-7488-x
Abstract
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)Keywords
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