Nerve growth factor promotes angiogenesis and arteriogenesis in ischemic hindlimbs
Nerve growth factor promotes angiogenesis and arteriogenesis in ischemic hindlimbs
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DOI：
10.1161/01.cir.0000033971.56802.c5
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发表时间：
2002-10-22
期刊：
影响因子：
37.8
通讯作者：
Mededdu, P
中科院分区：
文献类型：
--
作者：
Emanueli, C;Salis, MB;Mededdu, P
神经营养因子神经生长因子（NGF）调节神经元的存活和分化。神经生长因子及其高亲和力受体在血管水平的表达以及神经生长因子刺激血管内皮细胞增殖的特性支持了其在新生血管形成中的意义。本研究探讨了内源性神经生长因子参与缺血的自发性修复反应。NGF诱导的新生血管形成的机制和治疗潜力进行了examined.Methods和Results-Unilateral肢体缺血产生的CD 1小鼠股动脉切除术。通过ELISA和免疫组化，我们证实了NGF及其高亲和力受体在缺血肌肉中上调。这种现象的功能相关性通过NGF中和抗体进行评估。慢性神经生长因子阻断废除自发毛细血管反应缺血和增加心肌细胞凋亡。然后，我们测试是否NGF管理可能发挥疗效。反复注射神经生长因子到缺血内收肌增加毛细血管和小动脉密度，减少内皮细胞和肌纤维凋亡，并加速灌注恢复，而不改变全身血流动力学。在normoperfused肌肉，NGF诱导的毛细血管形成被阻断血管内皮生长因子中和抗体，显性负Akt，或NO synthase inhibit 1 n. Conclusions-这些结果表明，神经生长因子在修复性新血管形成中起着重要作用。此外，生长因子的补充通过血管内皮生长因子-Akt-NO-介导的机制促进血管生成。在局部缺血的情况下，增强NGF通路刺激血管生成和动脉生成，从而加速血流动力学恢复。神经生长因子可能被设想为治疗缺血性血管疾病的实用靶点。
Background-The neurotrophin nerve growth factor (NGF) regulates neuron survival and differentiation. Implication in neovascularization is supported by statement of NGF and its high-affinity receptor at vascular level and by NGF property of stimulating vascular endothelial cell proliferation. The present study investigated the involvement of endogenous NGF in spontaneous reparative response to ischemia. Mechanisms and therapeutic potential of NGF-induced neovascularization were examined.Methods and Results-Unilateral limb ischemia was produced in CD1 mice by femoral artery resection. By ELISA and immunohistochemistry, we documented that statement of NGF and its high-affinity receptor is upregulated in ischemic muscles. The functional relevance of this phenomenon was assessed by means of NGF-neutralizing antibody.. Chronic NGF blockade abrogated the spontaneous capillarization response to ischemia and augmented myocyte apoptosis. Then we tested whether NGF administration may exert curative effects. Repeated NGF injection into ischemic adductors increased capillary and arteriole density, reduced endothelial cell and myofiber apoptosis, and accelerated perfusion recovery, without altering systemic hemodynamics. In normoperfused muscles, NFG-induced capillarization was blocked by vascular endothelial growth factor-neutralizing antibodies, dominant-negative Akt, or NO synthase inhibition.Conclusions-These results indicate that NGF plays a functional role in reparative neovascularization. Furthermore, supplementation of the growth factor promotes angiogenesis through a vascular endothelial growth factor-Akt-NO-mediated mechanism. In the setting of ischemia, potentiation of NGF pathway stimulates angiogenesis and arteriogenesis, thereby accelerating hemodynamic recovery. NGF might be envisaged as a utilitarian target for the treatment of ischemic vascular disease.