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(Circulation Research. 2008;103:e15.)
© 2008 American Heart Association, Inc.

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Neurotrophin p75 Receptor (p75^NTR) Promotes Endothelial Cell Apoptosis and Inhibits Angiogenesis

Implications for Diabetes-Induced Impaired Neovascularization in Ischemic Limb Muscles

Andrea Caporali^*, Elisabetta Pani^*, Anton J.G. Horrevoets, Nicolle Kraenkel, Atsuhiko Oikawa, Graciela B. Sala-Newby, Marco Meloni, Brunella Cristofaro, Gallia Graiani, Aurelie S. Leroyer, Chantal M. Boulanger, Gaia Spinetti, Sung Ok Yoon, Paolo Madeddu, Costanza Emanueli

From the Experimental Cardiovascular Medicine (A.C., E.P., N.K., A.O., M.M., B.C., P.M., C.E.) and Vascular Biology Divisions (G.B.S.-N.), Bristol Heart Institute, University of Bristol, UK; IRCCS Multimedica Hospital (E.P., G.S.), Milan, Italy; the Department of Molecular Cell Biology and Immunology (A.J.G.H.), VU University Medical Center Amsterdam, Netherlands; Pathology (G.G.), University of Parma, Italy; INSERM Cardiovascular Research Center (A.S.L., C.N.B.), Hôpital Lariboisière, Paris, France; and the Center for Molecular Neurobiology (S.O.Y.), Ohio State University, Columbus.

Correspondence to Costanza Emanueli, BSc, PhD, FAHA, Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, level 7, Upper Maudlin Road BS2 8HW Bristol, UK. E-mail Costanza.Emanueli{at}bristol.ac.uk

Diabetes impairs endothelial function and reparative neovascularization. The p75 receptor of neurotrophins (p75^NTR), which is scarcely present in healthy endothelial cells (ECs), becomes strongly expressed by capillary ECs after induction of peripheral ischemia in type-1 diabetic mice. Here, we show that gene transfer-induced p75^NTR expression impairs the survival, proliferation, migration, and adhesion capacities of cultured ECs and endothelial progenitor cells (EPCs) and inhibits angiogenesis in vitro. Moreover, intramuscular p75^NTR gene delivery impairs neovascularization and blood flow recovery in a mouse model of limb ischemia. These disturbed functions are associated with suppression of signaling mechanisms implicated in EC survival and angiogenesis. In fact, p75^NTR depresses the VEGF-A/Akt/eNOS/NO pathway and additionally reduces the mRNA levels of ITGB1 [beta (1) integrin], BIRC5 (survivin), PTTG1 (securin) and VEZF1. Diabetic mice, which typically show impaired postischemic muscular neovascularization and blood perfusion recovery, have these defects corrected by intramuscular gene transfer of a dominant negative mutant form of p75^NTR. Collectively, our data newly demonstrate the antiangiogenic action of p75^NTR and open new avenues for the therapeutic use of p75^NTR inhibition to combat diabetes-induced microvascular liabilities.

Key Words: neurotrophins • p75^NTR • VEGF-A • reparative neovascularization • limb ischemia

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