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(Circulation. 2007;115:752-762.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

Tumor Necrosis Factor- Receptor p75 Is Required in Ischemia-Induced Neovascularization

David A. Goukassian, MD, PhD; Gangjian Qin, MD; Christine Dolan, MS; Toshinori Murayama, MD, PhD; Marcy Silver, BS; Cynthia Curry, BS; Elizabeth Eaton, BS; Corinne Luedemann, BS; Hong Ma, BS; Takayuki Asahara, MD, PhD; Victor Zak, PhD; Shanu Mehta, MS; Aaron Burg, BS; Tina Thorne, MS; Raj Kishore, PhD; Douglas W. Losordo, MD

From the Division of Cardiovascular Diseases, Department of Medicine, Caritas St Elizabeth’s Medical Center, Boston, Mass (D.A.G., C.D., T.M., M.S., C.C., E.E., C.L., H.M., T.A., V.Z., S.M., A.B.); Department of Dermatology, Boston University School of Medicine, Boston, Mass (D.A.G.); and Feinberg Cardiovascular Research Institute and Program in Cardiovascular Regenerative Medicine, Division of Cardiovascular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine and Northwestern Memorial Hospital, Chicago, Ill (G.Q., T.T., R.K., D.W.L.).

Correspondence to David A. Goukassian, MD, PhD, Division of Cardiovascular Research, St Elizabeth’s Medical Center of Boston, 736 Cambridge St, Brighton, MA 02135 (e-mail dgoukass{at}bu.edu); or Douglas W. Losordo, MD, Feinberg Cardiovascular Research Institute and Northwestern Memorial Hospital, Tarry 12-703, 303 E Chicago Ave, Chicago, IL 60611 (e-mail d-losordo@northwestern.edu).

Received June 20, 2006; accepted November 22, 2006.

Background— Aging is a risk factor for coronary and peripheral artery disease. Tumor necrosis factor- (TNF-), a proinflammatory cytokine, is expressed in ischemic tissue and is known to modulate angiogenesis. Little is known about the role of TNF- receptors (TNFR1/p55 and TNFR2/p75) in angiogenic signaling.

Methods and Results— We studied neovascularization in the hindlimb ischemia model in young and old TNFR2/p75 knockout (p75KO) and wild-type age-matched controls. Between days 7 to 10 after hindlimb surgery, 100% of old p75KOs experienced autoamputation of the operated limbs, whereas none of the age-matched wild-type mice exhibited hindlimb necrosis. Poor blood flow recovery in p75KO mice was associated with increased endothelial cell apoptosis, decreased capillary density, and significant reductions in the expression of vascular endothelial growth factor and basic fibroblast growth factor-2 mRNA transcripts in ischemic tissue and in circulating endothelial progenitor cells. The number of circulating bone marrow–derived endothelial progenitor cells was significantly reduced in p75KO mice. Transplantation of wild-type bone marrow mononuclear cells into irradiated old p75KO mice 1 month before hindlimb surgery prevented limb loss.

Conclusions— Our present study suggests that ischemia-induced endothelial progenitor cell–mediated neovascularization is dependent, at least in part, on p75 TNF receptor expressed in bone marrow–derived cells. Specifically, endothelial cell/endothelial progenitor cell survival, vascular endothelial growth factor expression, endothelial progenitor cell mobilization from bone marrow, endothelial progenitor cell differentiation, and ultimately ischemia-induced collateral vessel development are dependent on signaling through TNFR2/p75. Furthermore, because TNFR2/p75 becomes an age-related limiting factor in postischemic recovery, it may be a potential gene target for therapeutic interventions in adult vascular diseases.

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