Issue 1, 2025

Sustained hypoxia but not intermittent hypoxia induces HIF-1α transcriptional response in human aortic endothelial cells

Abstract

Obstructive sleep apnea (OSA) is characterized by intermittent hypoxic environments at the cellular level and is an independent risk factor for the development of cardiovascular disease. Endothelial cell (EC) dysfunction precedes the development of cardiovascular disease; however, the mechanisms by which ECs respond to these intermittent hypoxic events are poorly understood. To better understand EC responses to hypoxia, we examined the effects of sustained hypoxia (SH) and intermittent hypoxia (IH) on the activation of HIF-1α in ECs. While SH stabilized HIF-1α and led to its nuclear localization, IH did not activate HIF-1α and the expression of its target genes. Using RNA-sequencing, we evaluated transcriptional responses of ECs to hypoxia. SH induced the expression of HIF-1α and hypoxia response genes, while IH affected cell-cycle regulation genes. A cytoscape protein–protein interaction network for EC response to hypoxia was created with differentially expressed genes. The network comprises cell-cycle regulation, inflammatory signaling via NF-κB and response to VEGF stimulus subnetworks on which SH and IH had distinct activities. As OSA is associated with elevated catecholamines, we investigated the effect of epinephrine on the EC response to SH and IH. Transcriptomic responses under IH and epinephrine revealed protein–protein interaction networks emphasizing distinct subnetworks, including cytokine-mediated TNFα signaling via NF-κB, Wnt/LRP/DKK signaling and cell cycle regulation. This study reveals differential transcriptomic responses under SH and IH characterised by HIF-1α transcriptional response induced only by SH, but not by IH. The study also features the potential molecular events that may occur at the vascular level in OSA.

Graphical abstract: Sustained hypoxia but not intermittent hypoxia induces HIF-1α transcriptional response in human aortic endothelial cells

Supplementary files

Article information

Article type
Research Article
Submitted
29 Jul 2024
Accepted
19 Oct 2024
First published
22 Oct 2024
This article is Open Access
Creative Commons BY license

Mol. Omics, 2025,21, 19-31

Sustained hypoxia but not intermittent hypoxia induces HIF-1α transcriptional response in human aortic endothelial cells

R. Cetin-Atalay, A. Y. Meliton, Y. Tian, K. A. Sun, P. S. Woods, K. W. D. Shin, T. Cho, A. Gileles-Hillel, R. B. Hamanaka and G. M. Mutlu, Mol. Omics, 2025, 21, 19 DOI: 10.1039/D4MO00142G

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements