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

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.

Multimodal measurement of glycocalyx degradation during coronary artery bypass grafting

“…This is in line with the perception that the endothelial glycocalyx serves as a key factor in maintaining homeostasis of the vascular endothelium (35,36). Even though a causal relationship cannot be established from our data, some evidence suggests that glycocalyx damage at least precedes impaired endothelial function as Richter et al showed that in septic children and in mouse models of sepsis, heparan sulfate levels peak prior to Ang-2 levels (37). Elevated Ang-2 concentrations have been associated with increased albuminuria which is associated with impaired pulmonary and renal function (38, 39).…”

Succinate metabolism and membrane reorganization drives the endotheliopathy and coagulopathy of traumatic hemorrhage

“…Persistent damage to the EG, likely due to both ongoing shedding as well as transcriptional down-regulation of glycocalyx components, is reported in trauma and other critical illness states (45,(75)(76)(77)(78). An increase in succinate metabolism has been reported to drive transcriptional alterations (31,56) in several cell types.…”

Injury-induced endotheliopathy: What you need to know

“…Activated leukocytes secrete soluble factors that can directly disrupt paracellular vascular endothelial cadherin linkages. Furthermore, recent data from Richter et al 25 demonstrate that heparan sulfate cleavage upregulates EC production of angiopoietin-2, resulting in suppression of Tie2 receptor–mediated maintenance of intercellular junction protein expression.…”