HIF1α‐induced Upregulation of KLF4 Promotes Migration of Human Vascular Smooth Muscle Cells under Hypoxia

Hypoxia-induced vascular smooth muscle cells (VSMCs) migration plays an important role in vascular remodeling and is implicated in vascular diseases, such as atherosclerosis and pulmonary hypertension. We previously observed the increased expression of kruppel-like factor 4 (KLF4) in VSMCs under hypoxia. However, whether the upregulation of KLF4 participates in hypoxia-induced VSMCs migration is still unknown. In this study, we demonstrated that KLF4 was an important player in the process of VSMCs migration under hypoxia since interference of KLF4 by small interfering RNA mostly dampened hypoxia-induced migration of VSMCs. In addition, using luciferase reporter and ChIP assays, we confirmed two hypoxia-inducible factor 1 alpha (HIF1 alpha) binding elements (located at -150 to -163 and -3922 to -3932) in the upstream regulatory region of klf4 locus and identified KLF4 as a novel direct target gene of HIF1 alpha. Our findings unveil a novel regulatory mechanism that involves HIF1 alpha-induced upregulation of KLF4, which plays a vital role in VSMCs migration under hypoxia.