Neuropeptide Y induces ischemic angiogenesis and restores fimction of ischemic skeletal muscles
Neuropeptide Y induces ischemic angiogenesis and restores fimction of ischemic skeletal muscles
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DOI：
10.1172/jci200316929
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发表时间：
2003-06-01
影响因子：
15.9
通讯作者：
Zukowska, Z
中科院分区：
文献类型：
--
作者：
Lee, EW;Michalkiewicz, M;Zukowska, Z
以前，我们表明，神经肽Y（NPY），交感血管收缩神经递质，刺激内皮细胞迁移，增殖和分化在体外。在这里，我们报告了NPY的行动，受体和介质在缺血性血管生成。在大鼠中，后肢缺血刺激交感神经NPY释放（通过腰交感神经切除术减弱）并上调NPY-Y2（Y2）受体和肽酶形成Y2/Y 5选择性激动剂。生理浓度的外源性NPY也诱导Y 5受体，刺激新血管形成，并恢复缺血肌肉血流量和性能。NPY介导的缺血性血管生成不能被选择性Y1受体拮抗剂阻止，但在Y2（-/-）小鼠中减少。Y2（-/-）小鼠的非缺血性肌肉血管分布也较低，而与WT对照组相比，NPY过表达大鼠的非缺血性肌肉血管分布增加。离体，NPY诱导的主动脉发芽在Y2（-/-）动脉瘤中显著减少，并且自发发芽在NPY-/-小鼠中严重受损。NPY介导的主动脉发芽，但不是细胞迁移/增殖，被阻断的抗胎肝激酶1抗体和取消在小鼠空eNOS。因此，NPY在生理浓度下通过激活Y2/Y 5受体和eNOS介导神经源性缺血性血管生成，部分原因是VEGF的释放。NPY在缺血组织的再血管化和恢复功能中的有效性表明其在缺血状况中的治疗潜力。
Previously we showed that neuropeptide Y (NPY), a sympathetic vasoconstrictor neurotransmitter, stimulates endothelial cell migration, proliferation, and differentiation in vitro. Here, we report on NPY's actions, receptors, and mediators in ischemic angiogenesis. In rats, hindlimb ischemia stimulates sympathetic NPY release (attenuated by lumbar sympathectomy) and upregulates NPY-Y2 (Y2) receptor and a peptidase forming Y2/Y5-selective agonist. Exogenous NPY at physiological concentrations also induces Y5 receptor, stimulates neovascularization, and restores ischemic muscle blood flow and performance. NPY-mediated ischemic angiogenesis is not prevented by a selective Y1 receptor antagonist but is reduced in Y2(-/-) mice. Nonischemic muscle vascularity is also lower in Y2(-/-) mice, whereas it is increased in NPY-overexpressing rats compared with their WT controls. Ex vivo, NPY-induced aortic sprouting is markedly reduced in Y2(-/-) aortas and spontaneous sprouting is severely impaired in NPY-/- mice. NPY-mediated aortic sprouting, but not cell migration/proliferation, is blocked by an antifetal liver kinase 1 antibody and abolished in mice null for eNOS. Thus, NPY mediates neurogenic ischemic angiogenesis at physiological concentrations by activating Y2/Y5 receptors and eNOS, in part due to release of VEGF. NPY's effectiveness in revascularization and restoring function of ischemic tissue suggests its therapeutic potential in ischemic conditions.