Spinal vascular endothelial growth factor induces phrenic motor facilitation via extracellular signal-regulated kinase and Akt signaling.
Spinal vascular endothelial growth factor induces phrenic motor facilitation via extracellular signal-regulated kinase and Akt signaling.
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DOI：
10.1523/jneurosci.0239-11.2011
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发表时间：
2011-05-25
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影响因子：
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通讯作者：
Mitchell GS
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作者：
Dale-Nagle EA;Satriotomo I;Mitchell GS
尽管血管内皮生长因子 (VEGFA-165) 因其在血管生成中的作用而广为人知，但它也对脊髓运动神经元发挥重要的神经营养和神经保护作用。 VEGFA-165 通过激活其受体酪氨酸激酶 VEGF 受体 2 (VEGFR-2) 发出信号。由于另一种通过受体酪氨酸激酶（脑源性神经营养因子，BDNF）发出信号的生长/营养因子会引起膈神经呼吸运动活动的持久促进，因此我们测试了 VEGFA-165 引起类似膈运动促进（pMF）的假设。使用免疫组织化学和逆行标记技术，我们证明 VEGFA-165 和 VEGFR-2 在已识别的膈运动神经元中表达。此外，在 C4 处鞘内注射 VEGFA-165 可引发持久的 pMF；椎管内 VEGFA-165 增加注射后至少 90 分钟的综合膈神经爆发振幅（90 分钟时为 53.1±5.0%；p<0.001）。鞘内注射 VEGFA-165 增加膈运动核内 VEGFR-2 下游信号分子的磷酸化（和推测的激活），包括 ERK（对照大鼠中为 1.53±0.13AU 对比 1.0±0.05AU；p<0.05）和 Akt（对照大鼠中为 2.16±0.41AU 对比 1.0±0.41AU；p<0.05）。 VEGF 诱导的 pMF 被 MEK/ERK 抑制剂 U0126 减弱，并被 PI3 激酶/Akt 抑制剂 LY294002 消除，这表明 ERK MAP 激酶和 Akt 都是 VEGF 诱导的 pMF 完全表达所必需的。这是 VEGFA-165 在任何运动系统中引发可塑性的第一份报告。此外，由于 VEGFA-165 表达对缺氧敏感，因此它可能在长时间暴露于低氧后的呼吸可塑性中发挥作用。
Although vascular endothelial growth factor (VEGFA-165) is largely known for its role in angiogenesis, it also plays important neurotrophic and neuroprotective roles for spinal motor neurons. VEGFA-165 signals by activating its receptor tyrosine kinase, VEGF receptor-2 (VEGFR-2). Since another growth/trophic factor that signals via a receptor tyrosine kinase (brain derived neurotrophic factor, BDNF) elicits a long-lasting facilitation of respiratory motor activity in the phrenic nerve, we tested the hypothesis that VEGFA-165 elicits similar phrenic motor facilitation (pMF). Using immunohistochemistry and retrograde labeling techniques, we demonstrate that VEGFA-165 and VEGFR-2 are expressed in identified phrenic motor neurons. Further, intrathecal VEGFA-165 administration at C4 elicits long-lasting pMF; intraspinal VEGFA-165 increased integrated phrenic nerve burst amplitude for at least 90 min post-injection (53.1±5.0% at 90 min; p<0.001). Intrathecal VEGFA-165 increased phosphorylation (and presumed activation) of signaling molecules downstream from VEGFR-2 within the phrenic motor nucleus including ERK (1.53±0.13AU versus 1.0±0.05AU in control rats; p<0.05) and Akt (2.16±0.41AU versus 1.0±0.41AU in control rats; p<0.05). VEGF-induced pMF was attenuated by the MEK/ERK inhibitor U0126, and was abolished by the PI3 kinase/Akt inhibitor LY294002, demonstrating that ERK MAP kinases and Akt are both required for full expression of VEGF-induced pMF. This is the first report that VEGFA-165 elicits plasticity in any motor system. Further, since VEGFA-165 expression is hypoxia-sensitive, it may play a role in respiratory plasticity following prolonged exposures to low oxygen.