Skeletal muscle capillarity during hypoxia: VEGF and its activation
Skeletal muscle capillarity during hypoxia: VEGF and its activation
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DOI：
10.1089/ham.2008.1010
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发表时间：
2008-06-01
影响因子：
2.1
通讯作者：
Wagner, Peter
中科院分区：
文献类型：
--
作者：
Breen, Ellen;Tang, Kechun;Wagner, Peter
人类和许多哺乳动物长期暴露于缺氧导致骨骼肌内几种细胞机制的激活，这些机制补偿了有限的细胞氧可用性。这些细胞机制之一是增加低氧诱导基因的子集的表达，包括血管内皮生长因子（VEGF）的表达。VEGF启动子含有缺氧反应元件（HRE），其可以结合转录因子缺氧诱导因子-1 α（HIF-1 α），并启动VEGF基因的转录激活。VEGF基因表达对于骨骼肌血管生成至关重要，并且小鼠中的VEGF基因缺失已显示大大减少骨骼肌毛细血管。然而，VEGF基因的HIF-1 α依赖性转录激活可能不是导致急性或长期缺氧条件下VEGF水平升高或维持的唯一信号传导途径。在低氧暴露期间诱导的可能发出骨骼肌VEGF活化信号的其他机制包括炎症，可能与反应性O-2物质产生有关，或AMP激酶活性反映的细胞能量状态变化。这些途径可能提供了相当不同的机制VEGF上调的背景下，肌肉活动在长期暴露于低氧环境，如发生在高海拔地区。因此，这篇综述将讨论潜在的细胞信号或刺激导致缺氧暴露，可能会增加心肌细胞VEGF的表达。这些细胞信号包括1）细胞内P-O2减少，2）骨骼肌炎症、相关细胞因子和氧化应激，以及3）AMP激酶活性和腺苷增加，伴随细胞能量潜能降低。
Long-term exposure of humans and many mammals to hypoxia leads to the activation of several cellular mechanisms within skeletal muscles that compensate for a limited availability of cellular oxygen. One of these cellular mechanisms is to increase the expression of a subset of hypoxia-inducible genes, including the expression of vascular endothelial growth factor (VEGF). The VEGF promoter contains a hypoxic response element (HRE) that can bind the transcription factor, hypoxia-inducible factor-1 alpha; (HIF-1 alpha), and initiate transcriptional activation of the VEGF gene. VEGF gene expression is critically important for skeletal muscle angiogenesis and VEGF gene deletion in the mouse has been shown to greatly reduce skeletal muscle capillarity. However, HIF-1 alpha-dependent transcriptional activation of the VEGF gene may not be the only signaling pathway that leads to increased or maintained VEGF levels under conditions of acute or long-term hypoxia. Additional mechanisms, induced during hypoxic exposure that could signal skeletal muscle VEGF activation include inflammation, possibly linked to reactive O-2 species generation, or a change in cellular energy status as reflected by AMP kinase activity. These pathways may provide quite different mechanisms for VEGF upregulation in the context of muscular activity during long-term exposure to a hypoxic environment such as occurs at high altitude. This review will accordingly discuss the potential cellular signals or stimuli resulting from hypoxic exposure that could increase myocyte VEGF expression. These cellular signals include 1) a decrease in intracellular P-O2, 2) skeletal muscle inflammation, associated cytokines and oxidative stress, and 3) an increase in AMP kinase activity and adenosine accompanying a reduction in cellular energy potential.