Hypoxia triggers endothelial endoplasmic reticulum stress and apoptosis via induction of VLDL receptor

• In the present study, we detected the role of VLDLr in regulation of endothelial ER stress and apoptosis in the condition of hypoxia.
• We found that hypoxia triggered endothelial ER stress and apoptosis, and induced VLDLr expression.
• Silencing or stabilization of HIF-1α reduced or enhanced VLDLr expression, respectively. HIF-1α affected vldlr promoter activity via a hypoxia-responsive element.
• Knockdown or overexpression of VLDLr alleviated or exacerbated hypoxia-induced ER stress and apoptosis, respectively.
• Thus, hypoxia induces VLDLr expression through a HIF-1α-dependent style, and VLDLr mediates endothelial ER stress and apoptosis.

Endothelial cells express very low density lipoprotein receptor (VLDLr). Beyond the function as peripheral lipoprotein receptor, other roles of VLDLr in endothelial cells have not been completely unraveled. In the present study, human umbilical vein endothelial cells were subjected to hypoxia, and VLDLr expression, endoplasmic reticulum (ER) stress, and apoptosis were assessed. Hypoxia triggered endothelial ER stress and apoptosis, and induced VLDLr expression. Silencing or stabilization of HIF-1α reduced and enhanced VLDLr expression, respectively. HIF-1α affected vldlr promoter activity by interacting with a hypoxia-responsive element (HRE). Knockdown or overexpression of VLDLr alleviated and exacerbated hypoxia-induced ER stress and apoptosis, respectively. Thus, hypoxia induces VLDLr expression through the interaction of HIF-1α with HRE at the vldlr promoter. VLDLr then mediates ER stress and apoptosis.