title: The matricellular protein thrombospondin-1 globally regulates cardiovascular function and responses to stress via CD47.
abstract: Matricellular proteins play diverse roles in modulating cell behavior by engaging specific cell surface receptors and interacting with extracellular matrix proteins, secreted enzymes, and growth factors. Studies of such interactions involving thrombospondin-1 have revealed several physiological functions and roles in the pathogenesis of injury responses and cancer, but the relatively mild phenotypes of mice lacking thrombospondin-1 suggested that thrombospondin-1 would not be a central player that could be exploited therapeutically. Recent research focusing on signaling through its receptor CD47, however, has uncovered more critical roles for thrombospondin-1 in acute regulation of cardiovascular dynamics, hemostasis, immunity, and mitochondrial homeostasis. Several of these functions are mediated by potent and redundant inhibition of the canonical nitric oxide pathway. Conversely, elevated tissue thrombospondin-1 levels in major chronic diseases of aging may account for the deficient nitric oxide signaling that characterizes these diseases, and experimental therapeutics targeting CD47 show promise for treating such chronic diseases as well as acute stress conditions that are associated with elevated thrombospondin-1 expression.
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA. droberts@helix.nih.gov
authors.forename: David D
authors.initials: DD
authors.lastname: Roberts
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Miller
authors.forename: Natasha M
authors.initials: NM
authors.lastname: Rogers
authors.forename: Mingyi
authors.initials: M
authors.lastname: Yao
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Isenberg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051928:CD47 Antigen / Q000737:chemistry*; D002320:Cardiovascular Physiological Phenomena; D002319:Cardiovascular System / Q000737:chemistry* / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000737:chemistry; D011485:Protein Binding; D025941:Protein Interaction Mapping; D020239:Receptor Cross-Talk; D015398:Signal Transduction; D013312:Stress, Physiological; D019700:Thrombospondin 1 / Q000737:chemistry* / Q000502:physiology
chemical_list: D051928:CD47 Antigen; C497894:CD47 protein, human; C497895:Cd47 protein, mouse; D019700:Thrombospondin 1; D009569:Nitric Oxide