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Author Notes:

Correspondence to Paul C. Evans, PhD, Department of Cardiovascular Science, Medical School, University of Sheffield, Beech Hill Rd, Sheffield S10 2RX, United Kingdom. E-mail: paul.evans@sheffield.ac.uk

This manuscript was sent to Karin E. Bornfeldt, Consulting Editor, for review by expert referees, editorial decision, and final disposition.

These authors contributed equally to this article.

We thank Fiona Wright (University of Sheffield) for technical support.


Research Funding:

S. Feng, N. Bowden, V. Ridger, and P.C. Evans are funded by the British Heart Foundation (RG/13/1/30042). M. Fragiadaki is funded by Kidney Research UK. S. Allen is funded by the Motor Neurone Disease Association.

H. Jo’s work was supported, in part, by funding from National Institutes of Health grants HL095070 and John and Jan Portman Professorship.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Hematology
  • Peripheral Vascular Disease
  • Cardiovascular System & Cardiology
  • apolipoproteins E
  • atherosclerosis
  • endothelial cells
  • glycolysis
  • hypoxia-inducible factor 1

Mechanical Activation of Hypoxia-Inducible Factor 1 alpha Drives Endothelial Dysfunction at Atheroprone Sites

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Journal Title:

Arteriosclerosis, Thrombosis, and Vascular Biology


Volume 37, Number 11


, Pages 2087-+

Type of Work:

Article | Final Publisher PDF


OBJECTIVE: Atherosclerosis develops near branches and bends of arteries that are exposed to low shear stress (mechanical drag). These sites are characterized by excessive endothelial cell (EC) proliferation and inflammation that promote lesion initiation. The transcription factor HIF1α (hypoxia-inducible factor 1α) is canonically activated by hypoxia and has a role in plaque neovascularization. We studied the influence of shear stress on HIF1α activation and the contribution of this noncanonical pathwa y to lesion initiation. APPROACH AND RESULTS: Quantitative polymerase chain reaction and en face staining revealed that HIF1α was expressed preferentially at low shear stress regions of porcine and murine arteries. Low shear stress induced HIF1α in cultured EC in the presence of atmospheric oxygen. The mechanism involves the transcription factor nuclear factor-κB that induced HIF1α transcripts and induction of the deubiquitinating enzyme Cezanne that stabilized HIF1α protein. Gene silencing revealed that HIF1α enhanced proliferation and inflammatory activation in EC exposed to low shear stress via induction of glycolysis enzymes. We validated this observation by imposing low shear stress in murine carotid arteries (partial ligation) that upregulated the expression of HIF1α, glycolysis enzymes, and inflammatory genes and enhanced EC proliferation. EC-specific genetic deletion of HIF1α in hypercholesterolemic apolipoprotein E-defecient mice reduced inflammation and endothelial proliferation in partially ligated arteries, indicating that HIF1α drives inflammation and vascular dysfunction at low shear stress regions. CONCLUSIONS: Mechanical low shear stress activates HIF1α at atheroprone regions of arteries via nuclear factor-κB and Cezanne. HIF1α promotes atherosclerosis initiation at these sites by inducing excessive EC proliferation and inflammation via the induction of glycolysis enzymes.

Copyright information:

© 2017 The Authors.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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