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Glycocalyx heparan sulfate cleavage promotes endothelial cell angiopoietin-2 expression by impairing shear stress–related AMPK/FoxO1 signaling
Robert P. Richter, … , Amit Gaggar, Jillian R. Richter
Robert P. Richter, … , Amit Gaggar, Jillian R. Richter
Published June 28, 2022
Citation Information: JCI Insight. 2022;7(15):e155010. https://doi.org/10.1172/jci.insight.155010.
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Research Article Vascular biology

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

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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. Second, 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 (HLMVECs). We found that plasma HS levels peaked before plasma Ang-2 levels in children and mice with sepsis. Further, we discovered that impaired AMPK signaling contributed to increased Ang-2 expression following HS cleavage from flow-conditioned HLMVECs, establishing a paradigm by which Ang-2 may be upregulated during sepsis.

Authors

Robert P. Richter, Amit R. Ashtekar, Lei Zheng, Danielle Pretorius, Tripathi Kaushlendra, Ralph D. Sanderson, Amit Gaggar, Jillian R. Richter

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Figure 1

Plasma HS levels in children with sepsis peak at the time of PICU admission and correlate with plasma Ang-2 levels 24 hours after admission.

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Plasma HS levels in children with sepsis peak at the time of PICU admiss...
(A) Plasma HS levels in children with sepsis at 0, 24, 48, and 72 hours following admission to the PICU compared with healthy controls (HC) (controls, n = 39; sepsis, 0 hours and 24 hours n = 38, 48 hours n = 33, 72 hours n = 30). **P < 0.01, versus control. (B) Plasma levels of heparanase activity were significantly elevated at PICU admission in 10 randomly chosen patients with sepsis compared with 10 randomly selected controls, corresponding with the elevations in plasma HS levels in children with sepsis at the time of PICU admission. ***P < 0.001. (C) Spearman’s rank-order correlation between plasma HS levels measured at PICU admission (0 hours) and plasma Ang-2 levels 24 hours after PICU admission in children with sepsis. Data are presented as medians with interquartile ranges and analyzed by ordinary 1-way Kruskal-Wallis ANOVA corrected by Dunn’s multiple comparisons test (A) or by Mann-Whitney U test (B).

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