title: Extracellular Vesicles from Caveolin-Enriched Microdomains Regulate Hyaluronan-Mediated Sustained Vascular Integrity.
abstract: Defects in vascular integrity are an initiating factor in several disease processes. We have previously reported that high molecular weight hyaluronan (HMW-HA), a major glycosaminoglycan in the body, promotes rapid signal transduction in human pulmonary microvascular endothelial cells (HPMVEC) leading to barrier enhancement. In contrast, low molecular weight hyaluronan (LMW-HA), produced in disease states by hyaluronidases and reactive oxygen species (ROS), induces HPMVEC barrier disruption. However, the mechanism(s) of sustained barrier regulation by HA are poorly defined. Our results indicate that long-term (6-24 hours) exposure of HMW-HA induced release of a novel type of extracellular vesicle from HLMVEC called enlargeosomes (characterized by AHNAK expression) while LMW-HA long-term exposure promoted release of exosomes (characterized by CD9, CD63, and CD81 expression). These effects were blocked by inhibiting caveolin-enriched microdomain (CEM) formation. Further, inhibiting enlargeosome release by annexin II siRNA attenuated the sustained barrier enhancing effects of HMW-HA. Finally, exposure of isolated enlargeosomes to HPMVEC monolayers generated barrier enhancement while exosomes led to barrier disruption. Taken together, these results suggest that differential release of extracellular vesicles from CEM modulate the sustained HPMVEC barrier regulation by HMW-HA and LMW-HA. HMW-HA-induced specialized enlargeosomes can be a potential therapeutic strategy for diseases involving impaired vascular integrity.
authors.affiliation: Department of Medicine, Section of Pulmonary and Critical Care, Pritzker School of Medicine, The University of Chicago, Chicago, IL, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Mirzapoiazova
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, Pritzker School of Medicine, The University of Chicago, Chicago, IL, USA.
authors.forename: Frances E
authors.initials: FE
authors.lastname: Lennon
authors.affiliation: Department of Medicine, Section of Pulmonary and Critical Care, Pritzker School of Medicine, The University of Chicago, Chicago, IL, USA.
authors.forename: Bolot
authors.initials: B
authors.lastname: Mambetsariev
authors.affiliation: Department of Medicine, Section of Pulmonary and Critical Care, Pritzker School of Medicine, The University of Chicago, Chicago, IL, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Allen
authors.affiliation: Department of Medicine, Section of Pulmonary and Critical Care, Pritzker School of Medicine, The University of Chicago, Chicago, IL, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Riehm
authors.affiliation: Department of Surgery, Pritzker School of Medicine, The University of Chicago, Chicago, IL, USA.
authors.forename: Valeriy A
authors.initials: VA
authors.lastname: Poroyko
authors.affiliation: Department of Medicine, Section of Pulmonary and Critical Care, Pritzker School of Medicine, The University of Chicago, Chicago, IL, USA ; Department of Anesthesia and Critical Care, Pritzker School of Medicine, The University of Chicago, Chicago, IL, USA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Singleton