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

Satomi Hirose,Yugo Tabata,Kazuki Sone,Naoyuki Takahashi,Daisuke Yoshino,Kenichi Funamoto

doi:10.1080/19336918.2021.1978368

Abstract

ABSTRACT 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.

Highlights

Cells migrate by controlling cell-substrate and cell-cell adherent molecules through intracellular signaling and remodeling the cytoskeleton [1,2]
In this article, we provide evidence that p21-activated kinase (PAK) is involved in the regulatory mechanisms of hypoxiadependent cell migration. we investigated the oxygendependent collective migration of vascular endothelial cells and the underlying mechanisms involving the regulation of VE-cadherin, through the PAK pathway, and regulation by hypoxia-inducing factor (HIF)-1α
The migration velocity of vascular endothelial cells is oxygen dependent; it tends to increase by hypoxic exposure, while it decreases under an extremely low oxygen tension of ≤1% O2

Summary

Introduction

Cells migrate by controlling cell-substrate and cell-cell adherent molecules through intracellular signaling and remodeling the cytoskeleton [1,2]. Decreases in oxygen tension have been reported to cause angiogenesis by endothelial cells [14] and metastasis and proliferation of cancer cells [15] In vitro studies, such as wound healing (scratch) assays, have shown that a hypoxic environ ment encourages the migration of endothelial cells [20] and cancer cells [21]. By using custom-made microfluidic devices [13,25], we found that a hypoxic exposure of ~2% O2 causes increases in permeability [26] and collective cell migration [27] in a vascular endothelial cell monolayer These changes in endothelial behaviors and dynamics are caused in part by weakened cell adhesion as a result of hypoxiainduced internalization of vascular endothelial (VE)cadherin, a cell-cell adhesion molecule

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Conclusion