Increasing survival of ischemic tissue by targeting CD47.
Thrombospondin-1 (TSP1) limits the angiogenic and vasodilator activities of NO. This activity of TSP1 can be beneficial in some disease states, but endogenous TSP1 limits recovery of tissue perfusion following fixed ischemic injury in dorsal skin flaps in mice. Using mice lacking the TSP1 receptors CD36 or CD47, we now show that CD47 is the necessary receptor for limiting NO-mediated vascular smooth muscle relaxation and tissue survival following ischemic injury in skin flaps and hindlimbs. We further show that blocking CD47 or TSP1 using monoclonal antibodies and decreasing CD47 expression using an antisense morpholino oligonucleotide are effective therapeutic approaches to dramatically increase survival of soft tissue subjected to fixed ischemia. These treatments facilitate rapid vascular remodeling to restore tissue perfusion and increase skin and muscle viability. Thus, limiting CD47-dependent antagonism of NO-mediated vasodilation and vascular remodeling is a promising therapeutic modality to preserve tissues subject to ischemic stress.
Isenberg
Jeff S
JS
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892-1500, USA. isenberj@mail.nih.gov
Romeo
Martin J
MJ
Abu-Asab
Mones
M
Tsokos
Maria
M
Oldenborg
Anna
A
Pappan
Loretta
L
Wink
David A
DA
Frazier
William A
WA
Roberts
David D
DD
D000818:Animals; D051928:CD47 Antigen / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000639:trends*; D006614:Hindlimb / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007511:Ischemia / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D051928:CD47 Antigen; D004364:Pharmaceutical Preparations; D009569:Nitric Oxide