A novel angiogenic pathway mediated by non-neuronal nicotinic acetylcholine receptors
A novel angiogenic pathway mediated by non-neuronal nicotinic acetylcholine receptors
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DOI：
10.1172/jci200214676
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发表时间：
2002-08-01
影响因子：
15.9
通讯作者：
Cooke, JP
中科院分区：
文献类型：
--
作者：
Heeschen, C;Weis, M;Cooke, JP
我们最近报道尼古丁具有血管生成作用，这似乎是通过非神经性烟碱型乙酰胆碱受体(NAChRs)介导的。在这里，我们描述了内源性胆碱能血管生成的途径。在体外血管生成模型中，增加非选择性nAChR拮抗剂甲氨基甲胺的浓度完全和可逆地抑制内皮网络的形成。尽管内皮细胞上表达多种nAChR亚型，但只有选择性α7-nAChR拮抗剂α-银环蛇毒素有类似的抑制作用，而其他选择性拮抗剂对网络形成的抑制作用不明显。α7-nAChR在增殖、体外缺氧和体内缺血时表达上调。NAChR诱导的网络形成部分依赖于血管内皮生长因子，完全依赖于磷脂酰肌醇3-激酶和丝裂原活化蛋白激酶通路，最终导致核因子-kappaB的激活。在体内，药物抑制nAChR以及基因干扰α7-nAChR的表达显著抑制炎性血管生成，减少缺血诱导的血管生成和肿瘤生长。我们的结果提示，nAChRs可能在生理性和病理性血管生成中发挥重要作用。据我们所知，这是胆碱能血管生成途径的第一次描述，它为血管生成的治疗调控提供了一条新的途径。
We have recently reported that nicotine has angiogenic effects, which appear to be mediated through non-neuronal nicotinic acetylcholine receptors (nAChRs). Here, we describe the endogenous cholinergic pathway for angiogenesis. In an in vitro angiogenesis model, increasing concentrations of the nonselective nAChR antagonist mecamylamine completely and reversibly inhibited endothelial network formation. Although several nAChR isoforms are expressed on endothelial cells (ECs), a similar inhibition was only obtained with the selective alpha7-nAChR antagonist alpha-bungarotoxin, whereas other selective antagonists did not result in significant inhibition of network formation. alpha7-nAChR was upregulated during proliferation, by hypoxia in vitro, and by ischemia in vivo. The nAChR-induced network formation was partially dependent on VEGF, was completely dependent on the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways, and finally resulted in NF-kappaB activation. In vivo, pharmacological inhibition of nAChR as well as genetic disruption of alpha7-nAChR expression significantly inhibited inflammatory angiogenesis and reduced ischemia-induced angiogenesis and tumor growth. Our results suggest that nAChRs may play an important role in physiological and pathological angiogenesis. To our knowledge, this is the first description of a cholinergic angiogenic pathway, and it suggests a novel avenue for therapeutic modulation of angiogenesis.