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ResearchIn-Press PreviewVascular biology Open Access | 10.1172/jci.insight.155010

Glycocalyx heparan sulfate cleavage promotes endothelial cell angiopoietin-2 expression by impairing shear stress-related AMPK/FoxO1 signaling

Robert P. Richter,1 Amit R. Ashtekar,1 Lei Zheng,1 Danielle Pretorius,2 Tripathi Kaushlendra,3 Ralph D. Sanderson,3 Amit Gaggar,4 and Jillian R. Richter2

1Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

2Department of Surgery, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Pathology, University of Alabama at Birmingham, Birmingham, United States of America

4Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

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1Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

2Department of Surgery, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Pathology, University of Alabama at Birmingham, Birmingham, United States of America

4Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

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1Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

2Department of Surgery, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Pathology, University of Alabama at Birmingham, Birmingham, United States of America

4Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

Find articles by Zheng, L. in: JCI | PubMed | Google Scholar

1Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

2Department of Surgery, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Pathology, University of Alabama at Birmingham, Birmingham, United States of America

4Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

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1Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

2Department of Surgery, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Pathology, University of Alabama at Birmingham, Birmingham, United States of America

4Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

Find articles by Kaushlendra, T. in: JCI | PubMed | Google Scholar

1Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

2Department of Surgery, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Pathology, University of Alabama at Birmingham, Birmingham, United States of America

4Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

Find articles by Sanderson, R. in: JCI | PubMed | Google Scholar

1Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

2Department of Surgery, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Pathology, University of Alabama at Birmingham, Birmingham, United States of America

4Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

Find articles by Gaggar, A. in: JCI | PubMed | Google Scholar

1Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

2Department of Surgery, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Pathology, University of Alabama at Birmingham, Birmingham, United States of America

4Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

Find articles by Richter, J. in: JCI | PubMed | Google Scholar |

Published June 28, 2022 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.155010.
Copyright © 2022, Richter et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 28, 2022 - Version history
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Abstract

Angiopoietin-2 (Ang-2) is a key mediator of vascular disease during sepsis, and elevated plasma levels of Ang-2 are associated with organ injury scores and poor clinical outcomes. We have previously observed that biomarkers of endothelial glycocalyx (EG) damage correlate with plasma Ang-2 levels, suggesting a potential mechanistic linkage between EG injury and Ang-2 expression during states of systemic inflammation. However, the cell signaling mechanisms regulating Ang-2 expression following EG damage are unknown. In the current study, we determined the temporal associations between plasma heparan sulfate (HS) levels as a marker of EG erosion and plasma Ang-2 levels in children with sepsis and in mouse models of sepsis. Secondly, we evaluated the role of shear stress-mediated 5’-adenosine monophosphate-activated protein kinase (AMPK) signaling in Ang-2 expression following enzymatic HS cleavage from the surface of human primary lung microvascular endothelial cells (HLMVEC). We found that plasma HS levels peak prior to plasma Ang-2 levels in children and mice with sepsis. Further, we discovered that impaired AMPK signaling contributes to increased Ang-2 expression following HS cleavage from flow conditioned HLMVECs, establishing a novel paradigm by which Ang-2 may be upregulated during sepsis.

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