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

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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 of ITGB1 [beta (1) integrin] , BIRC5 (survivin ), PTTG 1 ( 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.