P21-activated kinase regulates oxygen-dependent migration of vascular endothelial cells in monolayers.

IF 3.3 3区 生物学 Q3 CELL BIOLOGY
Satomi Hirose, Yugo Tabata, Kazuki Sone, Naoyuki Takahashi, Daisuke Yoshino, Kenichi Funamoto
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引用次数: 3

Abstract

The collective migration of vascular endothelial cells plays important roles in homeostasis and angiogenesis. Oxygen concentration in vivo, which is lower than in the atmosphere and changes due to diseases, is a key factor affecting the cellular dynamics of vascular endothelial cells. We previously reported that hypoxic conditions promote the internalization of vascular endothelial (VE)-cadherin, a specific cell-cell adhesion molecule, and increase the velocity of the collective migration of vascular endothelial cells. However, the mechanism through which cells regulate collective migration as affected by oxygen tension is not fully understood. Here, we investigated oxygen-dependent collective migration, focusing on intracellular protein p21-activated kinase (PAK) and hypoxia-inducing factor (HIF)-1α. A monolayer of human umbilical vein vascular endothelial cells (HUVECs) was formed in a microfluidic device with controllability of oxygen tension. The HUVECs were then exposed to various oxygen conditions in a range from 0.8% to 21% O2, with or without PAK inhibition or chemical stabilization of HIF-1α. Collective cell migration was measured by particle image velocimetry with time-lapse phase-contrast microscopic images. Localizations of VE-cadherin and HIF-1α were quantified by immunofluorescent staining. The collective migration of HUVECs varied in an oxygen-dependent fashion; the migration speed was increased by hypoxic exposure down to 1% O2, while it decreased under an extremely low oxygen tension of less than 1% O2. PAK inhibition suppressed the hypoxia-induced increase of the migration speed by preventing VE-cadherin internalization into HUVECs. A decrease in the migration speed was also obtained by chemical stabilization of HIF-1α, suggesting that excessive accumulation of HIF-1α diminishes collective cell migration. These results indicate that the oxygen-dependent variation of the migration speed of vascular endothelial cells is mediated by the regulation of VE-cadherin through the PAK pathway, as well as other mechanisms via HIF-1α, especially under extreme hypoxic conditions.

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Abstract Image

Abstract Image

p21活化激酶调控单层血管内皮细胞的氧依赖性迁移。
血管内皮细胞的集体迁移在血管稳态和血管生成中起着重要作用。体内氧浓度低于大气中氧浓度并因疾病而发生变化,是影响血管内皮细胞动力学的关键因素。我们之前报道过,缺氧条件促进血管内皮(VE)-钙粘蛋白(一种特定的细胞-细胞粘附分子)的内化,并增加血管内皮细胞集体迁移的速度。然而,细胞调节受氧张力影响的集体迁移的机制尚不完全清楚。在这里,我们研究了氧依赖性集体迁移,重点关注细胞内蛋白p21活化激酶(PAK)和缺氧诱导因子(HIF)-1α。在氧张力可控的微流控装置中形成单层人脐静脉血管内皮细胞(HUVECs)。然后将HUVECs暴露于不同的氧气条件下,氧气浓度从0.8%到21%不等,有或没有PAK抑制或HIF-1α的化学稳定。集体细胞迁移是用粒子图像测速仪和时移相衬显微图像来测量的。免疫荧光染色定量VE-cadherin和HIF-1α的定位。HUVECs的集体迁移以氧依赖的方式变化;低氧暴露于1% O2时,迁移速度加快,而在低于1% O2的极低氧张力下迁移速度下降。PAK抑制通过阻止VE-cadherin内化到HUVECs中来抑制缺氧诱导的迁移速度的增加。HIF-1α的化学稳定也降低了迁移速度,这表明HIF-1α的过度积累减少了细胞的集体迁移。这些结果表明,血管内皮细胞迁移速度的氧依赖性变化是由VE-cadherin通过PAK途径调控,以及HIF-1α通过其他机制介导的,特别是在极端缺氧条件下。
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来源期刊
CiteScore
6.40
自引率
0.00%
发文量
7
审稿时长
53 weeks
期刊介绍: Cell Adhesion & Migration is a multi-disciplinary, peer reviewed open access journal that focuses on the biological or pathological implications of cell-cell and cell-microenvironment interactions. The main focus of this journal is fundamental science. The journal strives to serve a broad readership by regularly publishing review articles covering specific disciplines within the field, and by publishing focused issues that provide an overview on specific topics of interest within the field. Cell Adhesion & Migration publishes relevant and timely original research, as well as authoritative overviews, commentaries, and perspectives, providing context for the work presented in Cell Adhesion & Migration and for key results published elsewhere. Original research papers may cover all topics important in the field of cell-cell and cell-matrix interactions. Cell Adhesion & Migration also publishes articles related to cell biomechanics, biomaterial, and development of related imaging technologies.
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