title: CD47 is necessary for inhibition of nitric oxide-stimulated vascular cell responses by thrombospondin-1.
abstract: CD36 is necessary for inhibition of some angiogenic responses by the matricellular glycoprotein thrombospondin-1 and is therefore assumed to be the receptor that mediates its anti-angiogenic activities. Although ligation of CD36 by antibodies, recombinant type 1 repeats of thrombospondin-1, or CD36-binding peptides was sufficient to inhibit nitric oxide (NO)-stimulated responses in both endothelial and vascular smooth muscle cells, picomolar concentrations of native thrombospondin-1 similarly inhibited NO signaling in vascular cells from wild-type and CD36-null mice. Ligation of the thrombospondin-1 receptor CD47 by recombinant C-terminal regions of thrombospondin-1, thrombospondin-1 peptides, or CD47 antibodies was also sufficient to inhibit NO-stimulated phenotypic responses and cGMP signaling in vascular cells. Thrombospondin-1 did not inhibit NO signaling in CD47-null vascular cells or NO-stimulated vascular outgrowth from CD47-null muscle explants in three-dimensional cultures. Furthermore, the CD36-binding domain of thrombospondin-1 and anti-angiogenic peptides derived from this domain failed to inhibit NO signaling in CD47-null cells. Therefore, ligation of either CD36 or CD47 is sufficient to inhibit NO-stimulated vascular cell responses and cGMP signaling, but only CD47 is necessary for this activity of thrombospondin-1 at physiological concentrations.
authors.affiliation: Laboratory of Pathology, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Jeff S
authors.initials: JS
authors.lastname: Isenberg
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Ridnour
authors.forename: Julie
authors.initials: J
authors.lastname: Dimitry
authors.forename: William A
authors.initials: WA
authors.lastname: Frazier
authors.forename: David A
authors.initials: DA
authors.lastname: Wink
authors.forename: David D
authors.initials: DD
authors.lastname: Roberts
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D051928:CD47 Antigen / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D018919:Neovascularization, Physiologic; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D019700:Thrombospondin 1 / Q000378:metabolism*
chemical_list: D018955:CD36 Antigens; D051928:CD47 Antigen; D008024:Ligands; D010455:Peptides; D019700:Thrombospondin 1; D009569:Nitric Oxide; D006152:Cyclic GMP