Endothelial glycocalyx degradation during sepsis: Causes and consequences

Sullivan, R. C.; Rockstrom, Matthew; Schmidt, Eric P.; Hippensteel, Joseph A.

doi:10.1016/j.mbplus.2021.100094

Cited by 38 publications

(34 citation statements)

References 132 publications

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“…The protein-rich glycocalyx that lines the luminal surface of blood vessels is essential to maintain homeostatic endothelial cell signaling and vascular function (7)(8)(9). Heparan sulfate proteoglycans (HSPG) within the endothelial glycocalyx (EG) serve, among a host of functions, as transducers of apical surface shear stress to the endothelial intracellular environment impacting myriad downstream signaling pathways (10)(11)(12)(13)(14). Prior work suggests that the heparan sulfate (HS) side chains on EG HSPGs must remain intact to properly transmit surface shear stress to the endothelial intracellular environment (15,16).…”

Section: Introductionmentioning

confidence: 99%

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

Richter¹,

Ashtekar²,

Zheng³

et al. 2022

JCI Insight

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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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Section: Introductionmentioning

confidence: 99%

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

Richter¹,

Ashtekar²,

Zheng³

et al. 2022

JCI Insight

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“…In bacterial sepsis, the potential of HPSE and eGC as future pharmacological targets has already been highlighted (14,15,32). In detail, prevention of eGC damage by inhibition of HPSE significantly abolished vascular hyperpermeability and subsequent lung injury in murine endotoxemia (12).…”

Section: Discussionmentioning

confidence: 99%

Heparanase Is a Putative Mediator of Endothelial Glycocalyx Damage in COVID-19 – A Proof-of-Concept Study

et al. 2022

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Coronavirus disease 2019 (COVID-19) is a systemic disease associated with injury (thinning) of the endothelial glycocalyx (eGC), a protective layer on the vascular endothelium. The aim of this translational study was to investigate the role of the eGC-degrading enzyme heparanase (HPSE), which is known to play a central role in the destruction of the eGC in bacterial sepsis. Excess activity of HPSE in plasma from COVID-19 patients correlated with several markers of eGC damage and perfused boundary region (PBR, an inverse estimate of glycocalyx dimensions of vessels with a diameter 4-25 µm). In a series of translational experiments, we demonstrate that the changes in eGC thickness of cultured cells exposed to COVID-19 serum correlated closely with HPSE activity in concordant plasma samples (R = 0.82, P = 0.003). Inhibition of HPSE by a nonanticoagulant heparin fragment prevented eGC injury in response to COVID-19 serum, as shown by atomic force microscopy and immunofluorescence imaging. Our results suggest that the protective effect of heparin in COVID-19 may be due to an eGC-protective off-target effect.

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“…Cleavage of HSPGs and GAGs from the eGCX is a hallmark of vascular damage associated with many pathologic conditions, and plasma levels of shed HS and HSPG ectodomains have been investigated as prognostic biomarkers and measures of injury/illness severity [42] , [43] , [44] . As several recent review manuscripts extensively cover the mechanisms driving eGCX degradation resulting in vasculopathy [45] , [46] , [47] , herein we focus on structural eGCX remodeling that arises from alterations in endothelial HSPG biosynthesis and post-translational sulfation modifications to HS.…”

Section: Modifications To Egcx Hspgsmentioning

confidence: 99%

Alterations in heparan sulfate proteoglycan synthesis and sulfation and the impact on vascular endothelial function

Pretorius

Richter²,

Anand³

et al. 2022

Matrix Biology Plus

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Endothelial glycocalyx degradation during sepsis: Causes and consequences

Cited by 38 publications

References 132 publications

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

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

Heparanase Is a Putative Mediator of Endothelial Glycocalyx Damage in COVID-19 – A Proof-of-Concept Study

Alterations in heparan sulfate proteoglycan synthesis and sulfation and the impact on vascular endothelial function

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