Cell & Molecular Biology Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Mol Cell Neurosci. 2011 Feb;46(2):498-506. doi: 10.1016/j.mcn.2010.12.002. Epub 2010 Dec 9.
Communication between the vasculature and nervous system is important during embryogenesis but the molecular mechanisms mediating this are ill-defined. We evaluated the molecular mechanisms by which Nerve Growth Factor (NGF) and Brain-derived neurotrophic factor (BDNF) regulate VEGF production. NGF activation of TrkA causes a marked increase in VEGF secretion by neuronal cells. The NGF induced increase in VEGF is accompanied by an increase in HIF-1α. Pharmacologic inhibitors of the Trk tyrosine kinase, PI-3 kinase and mTOR paths prevent NGF stimulated increases in HIF-1α and VEGF. NGF induced increase in VEGF transcription is dependent on a hypoxia response element (HRE) in the VEGF promoter. Mutation of the HRE or siRNA mediated silencing of HIF-1α expression blocks NGF induced increases in VEGF transcription. In primary cultures of TrkA expressing neurons from dorsal root ganglion, NGF induces VEGF expression that is accompanied by increases in HIF-1α but not HIF-2α expression. In CGN neurons, BDNF induces VEGF that is dependent on induction of HIF-1α. Our study indicates that neurotrophin activation of Trk stimulates an increase in VEGF transcription that is mediated by induction of HIF-1α.
血管系统和神经系统之间的通讯在胚胎发生过程中很重要，但介导这种通讯的分子机制尚不清楚。我们评估了神经生长因子 (NGF) 和脑源性神经营养因子 (BDNF) 调节 VEGF 产生的分子机制。NGF 激活 TrkA 会导致神经元细胞 VEGF 分泌明显增加。NGF 诱导的 VEGF 增加伴随着 HIF-1α 的增加。Trk 酪氨酸激酶、PI-3 激酶和 mTOR 途径的药理学抑制剂可防止 NGF 刺激的 HIF-1α 和 VEGF 增加。NGF 诱导的 VEGF 转录增加依赖于 VEGF 启动子中的缺氧反应元件 (HRE)。HRE 突变或 siRNA 介导的 HIF-1α 表达沉默可阻断 NGF 诱导的 VEGF 转录增加。在来自背根神经节的 TrkA 表达神经元的原代培养物中，NGF 诱导 VEGF 表达，同时增加 HIF-1α 但不增加 HIF-2α 表达。在 CGN 神经元中，BDNF 诱导的 VEGF 依赖于 HIF-1α 的诱导。我们的研究表明，神经营养因子激活 Trk 刺激 VEGF 转录增加，这是通过诱导 HIF-1α 介导的。
