UAB Division of Trauma and Acute Surgery Assistant Professor Jillian Richter, Ph.D., alongside her colleagues including Department of Pediatrics Assistant Professor Robert Richter, M.D., published “Glycocalyx heparan sulfate cleavage promotes endothelial cell angiopoietin-2 expression by impairing shear stress-related AMPK/FoxO1 signaling” in The Journal of Clinical Investigation.
The research focus of Richter Lab at UAB is to understand the role of the endothelial glycocalyx (EG) in regulating injury severity and outcomes in injured and critically ill patients.
Richter Lab researchers have previously found that biomarkers of EG damage correlate with plasma Angiopoietin-2 (Ang-2) levels, suggesting a potential mechanistic linking between EG injury and Ang-2 expression that propagates vascular dysfunction during states of systemic inflammation.
The purpose of this new study was to validate the temporal association 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.
Another objective was to evaluate the role of HS as a mechanotransducer and regulator of Ang-2 expression via adenosine monophosphate-activated protein kinase (AMPK) signaling.
Researchers discovered that plasma HS levels peak prior to Ang-2 levels in children and mice with sepsis, and they showed that the severity of EG damage is proportional to the magnitude of subsequent Ang-2 release.
Researchers also found that impaired AMPK signaling contributes to increased Ang-2 expression following HS cleavage from flow conditioned human lung microvascular endothelial cells, establishing a novel paradigm by which Ang-2 may be upregulated during sepsis.
The study included 76 children. Half of the children were diagnosed with sepsis that were admitted to the Children’s of Alabama PICU between August 2018 and January 2020 and the control half were children presenting to the Children’s of Alabama outpatient dental rehabilitation clinic. Whole blood was collected at pediatric intensive care unit admission and 24, 48, and 72 hours after admission.
"This work illustrates the important impact of glycocalyx damage on mechanisms that promote endothelial cell dysfunction,” Richter said. “Ang-2 upregulation mediates vascular leak and organ failure in many types of critical illnesses, so uncovering the processes that regulate its expression could have implications for therapeutic strategies that extend beyond sepsis.”
UAB Division of Trauma and Acute Surgery collaborated with the UAB Division of Pediatrics and UAB Medicine. Support for the research was provided by the National Institutes of Health, the Kaul Pediatric Research Institute, and the University of Alabama Faculty Development Grant.
The other study Authors are:
- Amit Ashtekar, Ph.D., Scientist I
- Lei Zhang, M.S., Researcher IV
- Danielle Pretorius, Ph.D., Postdoctoral Researcher
- Kaushlendra Tripathi, M.S., Ph.D., Research Associate
- Ralph Sanderson, Ph.D., Endowed Professor of Cancer Pathobiology and Director of the Division of Molecular and Cellular Pathology
- Amit Gaggar, M.D., Ph.D., Professor