Blocking thrombospondin-1/CD47 signaling alleviates deleterious effects of aging on tissue responses to ischemia.
OBJECTIVE
Decreased blood flow secondary to peripheral vascular disease underlies a significant number of chronic diseases that account for the majority of morbidity and mortality among the elderly. Blood vessel diameter and blood flow are limited by the matricellular protein thrombospondin-1 (TSP1) through its ability to block responses to the endogenous vasodilator nitric oxide (NO). In this study we investigate the role TSP1 plays in regulating blood flow in the presence of advanced age and atherosclerotic vascular disease.


RESULTS
Mice lacking TSP1 or CD47 show minimal loss of their resistance to ischemic injury with age and increased preservation of tissue perfusion immediately after injury. Treatment of WT and apolipoprotein E-null mice using therapeutic agents that decrease CD47 or enhance NO levels reverses the deleterious effects of age- and diet-induced vasculopathy and results in significantly increased tissue survival in models of ischemia.


CONCLUSIONS
With increasing age and diet-induced atherosclerotic vascular disease, TSP1 and its receptor CD47 become more limiting for blood flow and tissue survival after ischemic injury. Drugs that limit TSP1/CD47 regulation of blood flow could improve outcomes from surgical interventions in the elderly and ameliorate vascular complications attendant to aging.
Isenberg
Jeff S
JS
MPH, Laboratory of Pathology, Building 10, 2A33, National Cancer Institute, Bethesda, Maryland 20892-1500, USA. isenberj@mail.nih.gov
Hyodo
Fuminori
F
Pappan
Loretta K
LK
Abu-Asab
Mones
M
Tsokos
Maria
M
Krishna
Murali C
MC
Frazier
William A
WA
Roberts
David D
DD
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001783:Blood Flow Velocity; D051928:CD47 Antigen / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D003097:Collateral Circulation; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000601:surgery; D006614:Hindlimb; D007511:Ischemia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D008026:Ligation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009336:Necrosis; D009569:Nitric Oxide / Q000378:metabolism; D016491:Peripheral Vascular Diseases / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012039:Regional Blood Flow; D015398:Signal Transduction; D019700:Thrombospondin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014664:Vasodilation
D001057:Apolipoproteins E; D051928:CD47 Antigen; C497895:Cd47 protein, mouse; D019700:Thrombospondin 1; D009569:Nitric Oxide; D006152:Cyclic GMP