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首页> 外文期刊>Endothelium: Journal of endothelial cell research >Angiostatin induces intracellular acidosis and anoikis in endothelial cells at a tumor-like low pH.
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Angiostatin induces intracellular acidosis and anoikis in endothelial cells at a tumor-like low pH.

机译：血管生成抑制素在类似肿瘤的低pH值下诱导内皮细胞发生细胞内酸中毒和无神经。

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Angiostatin inhibits angiogenesis by binding to endothelial cells (ECs) lining the vasculature of growing tumors. These cells are in a dynamic state during angiogenesis and are thus not firmly attached to the extracellular matrix. This makes them more vulnerable to anoikis, a process resulting in cell death initiated by or promoted by loss of attachment. Another potential source of EC vulnerability during tumor angiogenesis is that tumor extracellular pH is typically lower than in normal tissues. This presents an additional challenge to ECs in terms of maintaining ionic homeostasis. We report here that the lethality of angiostatin is significantly enhanced both by reduced matrix attachment during exposure and lowered extracellular pH (pH(e)). Another effect of angiostatin at reduced pH(e) is a decreased intracellular pH (pH(i)). These effects were observed in three model systems: aortic ring sprouts, ECs during tube formation, and ECs in a scratch/migration assay. In these three dynamic assays, angiostatin-induced cell death and intracellular acidification were clearly seen when pH(e) was reduced to 6.7. The intracellular acidification was far greater than that induced by pH(e) reduction alone. In contrast, the effect of angiostatin on pH(i) and on viability were not observed in a subconfluent monolayer in which the cells were allowed to attach to substrate for 48 h prior to exposure to angiostatin. These data suggest that low pH(e) and reduced adhesion to matrix play a role in the specificity of angiostatin for tumor neovasculature in contrast to wound healing and other normal angiogenic processes. The results also implicate roles for both pH(e) and pH(i) regulation in the mechanism of angiostatin action.
机译：血管抑素通过与内衬生长肿瘤的脉管系统的内皮细胞（EC）结合来抑制血管生成。这些细胞在血管生成过程中处于动态状态，因此不能牢固地附着在细胞外基质上。这使它们更容易受到神经过敏症的影响，该过程导致细胞死亡是由附着丧失引发的或由附着丧失引起的。肿瘤血管生成过程中EC脆弱性的另一个潜在来源是肿瘤细胞的pH通常低于正常组织中的pH。在维持离子稳态方面，这对ECs提出了另外的挑战。我们在这里报告说，通过减少暴露过程中的基质附着和降低的细胞外pH（pH（e）），血管抑素的致死率显着提高。血管抑素在降低的pH（e）下的另一个作用是降低细胞内pH（pH（i））。在三个模型系统中观察到了这些影响：主动脉环芽，管形成过程中的EC和刮擦/迁移分析中的EC。在这三个动态测定中，当pH（e）降至6.7时，可以清楚地看到血管抑素诱导的细胞死亡和细胞内酸化。细胞内酸化作用远大于仅通过pH（e）还原引起的作用。相反，在亚汇合单层中未观察到血管抑制素对pH（i）和活力的影响，在该亚汇合单层中，细胞在暴露于血管抑制素之前可附着至底物48小时。这些数据表明，与伤口愈合和其他正常血管生成过程相比，低pH（e）和对基质的粘附性降低在血管生成抑制素对肿瘤新血管的特异性中起作用。结果还暗示了pH（e）和pH（i）调节在血管抑素作用机理中的作用。

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