Neurotrophin p75 receptor (p75NTR) promotes endothelial cell apoptosis and inhibits angiogenesis: implications for diabetes-induced impaired neovascularization in ischemic limb muscles

Caporali, A. et al. (2008) Neurotrophin p75 receptor (p75NTR) promotes endothelial cell apoptosis and inhibits angiogenesis: implications for diabetes-induced impaired neovascularization in ischemic limb muscles. Circulation Research, 103(2), e15-e26. (doi:10.1161/CIRCRESAHA.108.177386)

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Publisher's URL: http://dx.doi.org/10.1161/CIRCRESAHA.108.177386

Abstract

Diabetes impairs endothelial function and reparative neovascularization. The p75 receptor of neurotrophins (p75NTR), 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 p75NTR expression impairs the survival, proliferation, migration, and adhesion capacities of cultured ECs and endothelial progenitor cells (EPCs) and inhibits angiogenesis in vitro. Moreover, intramuscular p75NTR 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, p75NTR depresses the VEGF-A/Akt/eNOS/NO pathway and additionally reduces the mRNA levels ofITGB1 [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 p75NTR. Collectively, our data newly demonstrate the antiangiogenic action of p75NTR and open new avenues for the therapeutic use of p75NTR inhibition to combat diabetes-induced microvascular liabilities.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Meloni, Dr Marco
Authors: Caporali, A., Pani, E., Horrevoets, A. J.G., Kraenkel, N., Oikawa, A., Sala-Newby, G. B., Meloni, M., Cristofaro, B., Graiani, G., Leroyer, A. S., Boulanger, C. M., Spinetti, G., Yoon, S. O., Madeddu, P., and Emanueli, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Circulation Research
Publisher:American Heart Association
ISSN:0009-7330
ISSN (Online):1524-4571|

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