Advisory Committee Chair
Amit Gaggar
Advisory Committee Members
James Blalock
Namasivayam Ambalavanan
Document Type
Thesis
Date of Award
1-1-2025
Degree Name by School
Master of Science (MS) Heersink School of Medicine
Abstract
Sepsis remains one of the most frequent causes of mortality and life-altering morbidity in humans of all ages globally. Though sepsis pathobiology is incompletely understood, it is clear that a unifying feature of all sepsis phenotypes is systemic vascular endotheliopathy and damage to the luminal glycocalyx of endothelial cells, or eGC, that leads to organ injury. While prior work has established that heparan sulfate (HS) is an especially important eGC constituent that helps regulate a host of endothelial cell (EC) functions, its role in promoting endotheliopathy during sepsis has not been fully characterized. Additionally, previous studies in the context of multiple myeloma have shown that small extracellular vesicles (EV) secreted from myeloma cells harbor heparanase (HPSE), the only known mammalian enzyme with activity on HS. However, HPSE+ EVs have not been characterized outside of cancer biology. As EVs are known to home select enzymes to specific tissues for targeted remodeling, HPSE+ EVs may have a role in causing HS damage in the eGC during sepsis. Thus, the objectives of our work were to (1) determine the impact of HS cleavage from the eGC on homeostatic EC signaling and gene expression and (2) characterize HPSE+ EVs within the plasma of humans with and without sepsis. We discovered that damage to HS in the eGC reduces homeostatic adenosine 5’-monophosphate-activated protein kinase signaling, which promotes an increase in angiopoietin-2 expression, a cytokine that promotes endothelial monolayer destabilization. We also uncovered that HS cleavage from the eGC disrupts homeostatic shear stress-responsive gene expression and reduces expression of genes that promote EC junctional integrity and cell polarity. Finally, we found that HPSE+ EVs circulate in healthy humans, constituting the bulk of total HPSE observed in human plasma, and that circulating levels of HPSE+ EVs decline during sepsis, coincident with reduced total levels of HPSE and increased levels of HS and angiopoietin-2 in the plasma of sepsis patients. Though our findings require more robust characterization and validation, they suggest a novel paradigm by which EVs are key drivers of sepsis-associated endotheliopathy. In the process of clarifying the mechanisms by which EVs contribute to endotheliopathy in sepsis, we hope to discover novel therapeutic targets for this disease.
Recommended Citation
Richter, Robert Patrick, "Uncovering The Role Of Heparanase-Armed Extracellular Vesicles In Sepsis-Associated Vascular Endotheliopathy" (2025). All ETDs from UAB. 6885.
https://digitalcommons.library.uab.edu/etd-collection/6885
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