Neurotrophin p75 receptor (p75^NTR) 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 (p75^NTR) 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)

Abstract

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 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 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.

• 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 > School of Cardiovascular & Metabolic Health
• Journal Name: Circulation Research
• Publisher: American Heart Association
• ISSN: 0009-7330
• ISSN (Online): 1524-4571|