Abstract
Circulating extracellular vesicles (EVs) are recognized as biomarkers and effectors of endothelial dysfunction, the initiating step of cardiovascular abnormalities. Among these EVs, microparticles (MPs) are vesicles directly released from the cytoplasmic membrane of activated cells. MPs were shown to induce endothelial dysfunction through the activation of endoplasmic reticulum (ER) stress. However, it is not known whether ER stress can lead to MPs release from endothelial cells and what biological messages are carried by these MPs. Therefore, we aimed to assess the impact of ER stress on MPs shedding from endothelial cells, and to investigate their effects on endothelial cell function. EA.hy926 endothelial cells or human umbilical vein endothelial cells (HUVECs) were treated for 24 h with ER stress inducers, thapsigargin or dithiothreitol (DTT), in the presence or absence of 4-Phenylbutyric acid (PBA), a chemical chaperone to inhibit ER stress. Then, MPs were isolated and used to treat cells (10–20 μg/mL) for 24–48 h before assessing ER stress response, angiogenic capacity, nitric oxide (NO) release, autophagy and apoptosis. ER stress (thapsigargin or DDT)-generated MPs did not differ quantitatively from controls; however, they carried deleterious messages for endothelial function. Exposure of endothelial cells to ER stress-generated MPs increased mRNA and protein expression of key ER stress markers, indicating a vicious circle activation of ER stress. ER stress (thapsigargin)-generated MPs impaired the angiogenic capacity of HUVECs and reduced NO release, indicating an impaired endothelial function. While ER stress (thapsigargin)-generated MPs altered the release of inflammatory cytokines, they did not, however, affect autophagy or apoptosis in HUVECs. This work enhances the general understanding of the deleterious effects carried out by MPs in medical conditions where ER stress is sustainably activated such as diabetes and metabolic syndrome.
Highlights
Maintaining optimal vascular homeostasis balance is very critical for the integrity of the cardiovascular tree to prevent the development of cardiovascular co-morbidities prevalent with metabolic diseases such as obesity and diabetes
Analysis of MPs isolated from various conditions showed no differences in amount of proteins associated with MPs isolated from EA.hy926 cells treated with DTT in the presence or absence of Phenylbutyric acid (PBA) (Figure 3A) or from human umbilical vein endothelial cells (HUVECs) incubated with TG in the in the presence or absence of PBA (Figure 3B)
MPs have strongly emerged as biomarkers and mediators of endothelial dysfunction in diabetes and very seldom evidence is showing the implication of endoplasmic reticulum (ER) stress activation in MP-induced endothelial dysfunction [20, 30, 31]
Summary
Maintaining optimal vascular homeostasis balance is very critical for the integrity of the cardiovascular tree to prevent the development of cardiovascular co-morbidities prevalent with metabolic diseases such as obesity and diabetes. Achieving balance between relaxing and contracting factors, and between antithrombotic and prothrombotic factors is important for the normal function of the vascular system. These functions are maintained by the endothelium, a thin layer of endothelial cells that line the entire vasculature. While apoptotic bodies (size > 1,000 nm) and MPs (size 100–1,000 nm) appear to have similar mechanisms of release which is outward blebbing and shedding of vesicles directly from the plasma membrane of apoptotic or activated cells, respectively [2, 3]
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