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

The collective migration of vascular endothelial cells plays important roles in homeostasis and angiogenesis. Oxygen tension in vivo is a key factor affecting the cellular dynamics. We previously reported hypoxic conditions promote the internalization of vascular endothelial (VE)-cadherin and increase 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. The 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.

血管内皮细胞的集体迁移在机体稳态与血管生成过程中发挥关键作用。体内氧分压是影响细胞动态行为的核心调控因素。我们既往研究证实，低氧条件可促进血管内皮钙黏蛋白（VE-cadherin）的内吞作用，并增强血管内皮细胞的集体迁移能力。然而，细胞如何调控受氧分压影响的集体迁移，其具体机制尚未完全明确。本研究针对氧依赖的集体迁移展开探究，重点关注胞内蛋白p21激活激酶（p21-activated kinase, PAK）与缺氧诱导因子（hypoxia-inducing factor, HIF）-1α。结果表明，血管内皮细胞迁移速度的氧依赖性变化，既通过PAK通路调控VE-cadherin实现，也存在其他经由HIF-1α的调控机制，尤其在极端低氧条件下更为显著。