Morphine stimulates vascular endothelial growth factor-like signaling in mouse retinal endothelial cells
Morphine stimulates vascular endothelial growth factor-like signaling in mouse retinal endothelial cells
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DOI：
10.2174/156720206778018767
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发表时间：
2006-08-01
影响因子：
2.1
通讯作者：
Gupta, Kalpna
中科院分区：
文献类型：
--
作者：
Chen, Chunsheng;Farooqui, Mariya;Gupta, Kalpna
GO/GI偶联G蛋白受体介导的反式激活在受体酪氨酸激酶(RTK)的激活中起关键作用。在这里，我们发现Mu阿片受体(MOR)反式激活Flk1和血小板衍生生长因子-β(PDGF-P)受体，其激动剂吗啡刺激小鼠视网膜内皮细胞(MREC)促血管生成和促进生存的信号转导。吗啡以剂量依赖的方式刺激mREC增殖，并促进存活，其程度与血管内皮生长因子(164)(血管内皮生长因子(164))相同。吗啡以时间依赖的方式刺激丝裂原激活的蛋白激酶/细胞外信号调节激酶(MAPK/ERK)和Akt的磷酸化，就像在mREC中的血管内皮生长因子一样。此外，与血管内皮生长因子类似，吗啡也能刺激致癌信号转导和转录激活子3(STAT3)信号传导。吗啡和血管内皮生长因子诱导的磷酸化STAT3和磷酸化Flk1与MOR相关蛋白免疫共沉淀。此外，吗啡还可刺激MOR相关的PDGF-β受体的磷酸化。与VEGF与MOR的关系一致，我们发现VEGF上调mREC中MOR蛋白和RNA的表达。这些数据表明，MOR结合并反式激活Flk1和PDGF-β的RTK，这可能对内皮血管生成信号具有复合效应。因此，包括MOR在内的G蛋白偶联受体为开发抗血管生成药物提供了新的靶点。
Go/Gi coupled G-protein receptor mediated transactivation is critical in the activation of receptor tyrosine kinases (RTK). Here we show that mu opioid receptor (MOR) transactivates Flk1 and platelet-derived growth factor-beta (PDGF-P) receptors and its agonist morphine stimulates pro-angiogenic and survival-promoting signaling in mouse retinal endothelial cells (mREC). Morphine stimulates mREC proliferation in a dose dependent fashion and promotes survival to the same extent as vascular endothelial growth factor(164) (VEGF(164)). Morphine stimulates mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and Akt phosphorylation in a time dependent manner like VEGF in mREC. Moreover, analogous to VEGF, morphine stimulates oncogenic signal transducer and activator of transcription 3 (STAT3) signaling. Morphine as well as VEGF-induced phospho-STAT3 and phospho-Flk1 immunoprecipitated with MOR-associated proteins. In addition morphine also stimulated MOR associated PDGF-beta receptor phosphorylation. Consistent with the relationship between VEGF and MOR we found that VEGF upregulates MOR protein and RNA expression in mREC. These data suggest that MOR associates and transactivates RTKs for Flk1 and PDGF-beta, which may have a compounding effect on angiogenic signaling in endothelium. Therefore, G-Protein coupled receptors including MOR provide novel targets to develop anti-angiogenic agents.