Department of Comparative Biosciences, University of Wisconsin, Madison, Wisconsin 53706, USA.
J Neurosci. 2011 May 25;31(21):7682-90. doi: 10.1523/JNEUROSCI.0239-11.2011.
Although vascular endothelial growth factor (VEGFA-165) is primarily 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). Because another growth/trophic factor that signals via a receptor tyrosine kinase (brain derived neurotrophic factor) 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. Furthermore, intrathecal VEGFA-165 administration at C4 elicits long-lasting pMF; intraspinal VEGFA-165 increased integrated phrenic nerve burst amplitude for at least 90 min after 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 ± 0.13 vs 1.0 ± 0.05 arbitrary units in control rats; p < 0.05) and Akt (2.16 ± 0.41 vs 1.0 ± 0.41 arbitrary units in control rats; p < 0.05). VEGF-induced pMF was attenuated by the MEK/ERK inhibitor U0126 [1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadiene] and was abolished by the phosphotidinositol 3 kinase/Akt inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride], demonstrating that ERK mitogen-activated protein 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. Furthermore, because VEGFA-165 expression is hypoxia sensitive, it may play a role in respiratory plasticity after prolonged exposures to low oxygen.
虽然血管内皮生长因子 (VEGFA-165) 主要因其在血管生成中的作用而闻名，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血管内皮生长因子受体-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) 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，因此我们测试了假设，即 VEGFA-165 会引起类似的膈神经运动促进 (pMF)。通过免疫组织化学和逆行标记技术，我们证明 VEGFA-165 和 VEGFR-2 表达在已识别的膈神经运动神经元中。此外，在 C4 鞘内给予 VEGFA-165 会引起持久的 pMF；脊髓内给予 VEGFA-165 会使膈神经爆发幅度的整合至少增加 90 分钟（90 分钟时为 53.1 ± 5.0%；p < 0.001）。鞘内给予 VEGFA-165 会增加膈运动核内 VEGFR-2 下游信号分子的磷酸化（和假定激活），包括 ERK（在对照大鼠中为 1.53 ± 0.13 对 1.0 ± 0.05 任意单位；p < 0.05）和 Akt（在对照大鼠中为 2.16 ± 0.41 对 1.0 ± 0.41 任意单位；p < 0.05）。VEGF 诱导的 pMF 被 MEK/ERK 抑制剂 U0126 [1,4-二氨基-2,3-二氰基-1,4-双（o-氨基苯硫代甲巯基）丁二烯] 减弱，被磷酯酰肌醇 3 激酶/Akt 抑制剂 LY294002 [2-(4-吗啉基)-8-苯基-1(4H)-苯并吡喃-4-酮盐酸盐] 消除，表明 ERK 有丝分裂原激活蛋白激酶和 Akt 均为 VEGF 诱导的 pMF 完全表达所必需。这是 VEGFA-165 引发任何运动系统可塑性的第一个报告。此外，由于 VEGFA-165 的表达对缺氧敏感，它可能在长时间暴露于低氧后发挥呼吸可塑性的作用。
