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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2582.)
© 2007 American Heart Association, Inc.

Vascular Biology

Blocking Thrombospondin-1/CD47 Signaling Alleviates Deleterious Effects of Aging on Tissue Responses to Ischemia

Jeff S. Isenberg; Fuminori Hyodo; Loretta K. Pappan; Mones Abu-Asab; Maria Tsokos; Murali C. Krishna; William A. Frazier; David D. Roberts

From the Laboratory of Pathology (J.S.I., M.A.A., M.T., D.D.R.) and Radiation Biology Branch (F.H., M.C.K.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Md; and the Department of Biochemistry and Molecular Biophysics (L.K.P., W.A.F.), Washington University School of Medicine, St. Louis, Mo.

Correspondence to Jeff S. Isenberg, MD, MPH, Laboratory of Pathology, Building 10, 2A33, National Cancer Institute, Bethesda, Maryland 20892-1500. E-mail isenberj{at}mail.nih.gov

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.

Methods and 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.

Conclusion— 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.

Decreased blood flow and wound healing are common in the elderly. Nitric oxide can increase both tissue blood flow and healing, but thrombospondin-1 limits responses to nitric oxide in aged mice. Blocking the thrombospondin-1 receptor CD47 restores blood flow and increases tissue healing.

Key Words: nitric oxide • thrombospondin-1 • perfusion • ischemia • wound healing

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