Neurotrophin p75 receptor (p75NTR) promotes endothelial cell apoptosis and inhibits angiogenesis -: Implications for diabetes-induced impaired neovascularization in ischemic limb muscles
Neurotrophin p75 receptor (p75NTR) promotes endothelial cell apoptosis and inhibits angiogenesis -: Implications for diabetes-induced impaired neovascularization in ischemic limb muscles
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DOI：
10.1161/circresaha.108.177386
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发表时间：
2008-07-18
影响因子：
20.1
通讯作者：
Emanueli, Costanza
中科院分区：
文献类型：
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作者：
Caporali, Andrea;Pani, Elisabetta;Emanueli, Costanza
糖尿病损害内皮功能和修复性新血管形成。神经营养因子的p75受体（p75（NTR））在健康内皮细胞（EC）中几乎不存在，在1型糖尿病小鼠中诱导外周缺血后，其在毛细血管EC中强烈表达。在这里，我们表明，基因转移诱导的p75（NTR）表达损害的生存，增殖，迁移和粘附能力培养的内皮细胞和内皮祖细胞（EPCs）和抑制血管生成在体外。此外，肌内p75（NTR）基因传递损害新血管形成和血流恢复的小鼠模型肢体缺血。这些干扰的功能与EC存活和血管生成中涉及的信号传导机制的抑制有关。事实上，p75（NTR）抑制VEGF-A/Akt/eNOS/NO通路，并额外降低ITGB 1 [β（1）整联蛋白]、BIRC 5（生存素）、PTTG 1（securin）和VEZF 1的mRNA水平。糖尿病小鼠通常表现出缺血后肌肉新生血管形成和血液灌注恢复受损，这些缺陷通过肌内基因转移显性失活突变形式的p75（NTR）得到纠正。总的来说，我们的数据新证明了p75（NTR）的抗血管生成作用，并为p75（NTR）抑制治疗糖尿病诱导的微血管负债开辟了新的途径。
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.