Endothelium has a rich vesicular network that allows the exchange of macromolecules between blood and parenchymal cells. This feature of endothelial cells, along with their polarized secretory machinery, makes them the second major contributor, after platelets, to the particulate secretome in circulation. Extracellular vesicles (EVs) produced by the endothelial cells mirror the remarkable molecular heterogeneity of their parent cells. Cargo molecules carried by EVs were shown to contribute to the physiological functions of endothelium and may support the plasticity and adaptation of endothelial cells in a paracrine manner. Endothelium-derived vesicles can also contribute to the pathogenesis of cardiovascular disease or can serve as prognostic or diagnostic biomarkers. Finally, endothelium-derived EVs can be used as therapeutic tools to target endothelium for drug delivery or target stromal cells via the endothelial cells. In this review we revisit the recent evidence on the heterogeneity and plasticity of endothelial cells and their EVs. We discuss the role of endothelial EVs in the maintenance of vascular homeostasis along with their contributions to endothelial adaptation and dysfunction. Finally, we evaluate the potential of endothelial EVs as disease biomarkers and their leverage as therapeutic tools.
Cardiovascular disease (CVD) is the most prominent cause of death of adults in the United States with coronary artery disease being the most common type of CVD. Following a myocardial event, the coronary endothelium plays an important role in the recovery of the ischemic myocardium. Specifically, endothelial cells (EC) must be able to elicit a robust angiogenic response necessary for tissue revascularization and repair. However, local or distant cues may prevent effective revascularization. Extracellular vesicles (EV) are produced by all cells and endothelium is a rich source of EVs that have access to the main circulation thereby potentially impacting local and distant tissue function. Systemic inflammation associated with conditions such as obesity as well as the acute inflammatory response elicited by a cardiac event can significantly increase the EV release by endothelium and alter their miRNA, protein or lipid cargo. Our laboratory has previously shown that EVs released by adipose tissue endothelial cells exposed to chronic inflammation have angiostatic effects on naïve adipose tissue EC in vitro. Whether the observed effect is specific to EVs from adipose tissue endothelium or is a more general feature of the endothelial EVs exposed to pro-inflammatory cues is currently unclear. The objective of this study was to investigate the angiostatic effects of EVs produced by EC from the coronary artery and adipose microvasculature exposed to pro-inflammatory cytokines (PIC) on naïve coronary artery EC. We have found that EVs from both EC sources have angiostatic effects on the coronary endothelium. EVs produced by cells in a pro-inflammatory environment reduced proliferation and barrier function of EC without impacting cellular senescence. Some of these functional effects could be attributed to the miRNA cargo of EVs. Several miRNAs such as miR-451, let-7, or miR-23a impact on multiple pathways responsible for proliferation, cellular permeability and angiogenesis. Collectively, our data suggests that EVs may compete with pro-angiogenic cues in the ischemic myocardium therefore slowing down the repair response. Acute treatments with inhibitors that prevent endogenous EV release immediately after an ischemic event may contribute to better efficacy of therapeutic approaches using functionalized exogenous EVs or other pro-angiogenic approaches.
Endothelial cells (EC) are major contributors to the extracellular vesicles (EV) pool in systemic circulation. EVs released by vascular endothelium of different phenotypes mirror their molecular heterogeneity. Our laboratory showed that EVs released by human adipose tissue ECs exposed to chronic inflammation have angiostatic effects on naïve, proliferating ECs from adipose tissue in vitro. Whether the observed effect is specific to EVs from adipose tissue endothelium or is a more general feature of the endothelial EVs exposed to pro‐inflammatory cues is currently unclear. Coronary circulation is critical for recovery of the ischemic myocardium and effective angiogenesis is key to support an adequate repair response. In this study, we compared the proliferative and angiogenic effects and cargo composition of EVs produced by ECs from coronary artery and adipose microvasculature exposed to prolonged treatment with pro‐inflammatory cytokines (PIC) on naïve coronary artery ECs. To mimic the pro‐inflammatory environment in vivo, ECs were treated for 6 days with a combination of TNFa, interferon g, and TGFb (5nM each). EVs were collected from conditioned media and separated using differential ultracentrifugation. Typically, vesicles produced by both adipose and coronary ECs exposed to PIC, produced ~2‐fold more EVs/cell, and the size range for all EVs used in experiments was between 40‐200nm. EVs from coronary EC had the most potent anti‐proliferative effect that was time‐dependent. After 24 hours of incubation with EVs produced by PIC‐treated coronary ECs, proliferation of the naïve coronary ECs was reduced by ~80%, as assessed by BrdU incorporation. The reduced proliferation was not due to cellular senescence. Cells treated with EVs isolated from both adipose and coronary ECs showed reduced in vitro angiogenic responses, in the presence of VEGF, compared to untreated control cells. While all EV treatments were angiostatic, the magnitude of the effects was different for different EV preparations. Specifically, coronary cells treated with autologous EVs produced in response to PIC treatment displayed the most prominent reduction in the angiogenic response to VEGF, measured in vitro as tubule formation. Interestingly, the proteome of EVs produced by adipose ECs after prolonged cytokine treatment contained peptide signatures for all VEGF receptors, including VEGFR2. Immunogold EM showed VEGFR2 positivity on the membrane of some of the EVs produced following PIC treatment of the parent cells. We are currently investigating whether EVs may function as soluble decoy receptors that can exert their angiostatic effect via binding of circulating VEGF. The angiostatic effect of autologous EVs on coronary endothelium may be physiologically meaningful in post‐ischemic myocardial events when such EVs may prevent or delay a robust angiogenic response needed for tissue re‐vascularization.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.