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Apoptotic exosome-like vesicles regulate endothelial gene expression, inflammatory signaling, and function through the NF-?B signaling pathway.

ABSTRACT: Persistent endothelial injury promotes maladaptive responses by favoring the release of factors leading to perturbation in vascular homeostasis and tissue architecture. Caspase-3 dependent death of microvascular endothelial cells leads to the release of unique apoptotic exosome-like vesicles (ApoExo). Here, we evaluate the impact of ApoExo on endothelial gene expression and function in the context of a pro-apoptotic stimulus. Endothelial cells exposed to ApoExo differentially express genes involved in cell death, inflammation, differentiation, and cell movement. Endothelial cells exposed to ApoExo showed inhibition of apoptosis, improved wound closure along with reduced angiogenic activity and reduced expression of endothelial markers consistent with the first phase of endothelial-to-mesenchymal transition (endoMT). ApoExo interaction with endothelial cells also led to NF-?B activation. NF-?B is known to participate in endothelial dysfunction in numerous diseases. Silencing NF-?B reversed the anti-apoptotic effect and the pro-migratory state and prevented angiostatic properties and CD31 downregulation in endothelial cells exposed to ApoExo. This study identifies vascular injury-derived extracellular vesicles (ApoExo) as novel drivers of NF-?B activation in endothelial cells and demonstrates the pivotal role of this signaling pathway in coordinating ApoExo-induced functional changes in endothelial cells. Hence, targeting ApoExo-mediated NF-?B activation in endothelial cells opens new avenues to prevent endothelial dysfunction.

SUBMITTER: Migneault F

PROVIDER: S-EPMC7387353 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Apoptotic exosome-like vesicles regulate endothelial gene expression, inflammatory signaling, and function through the NF-κB signaling pathway.

Migneault Francis F Dieudé Mélanie M Turgeon Julie J Beillevaire Déborah D Hardy Marie-Pierre MP Brodeur Alexandre A Thibodeau Nicolas N Perreault Claude C Hébert Marie-Josée MJ

Scientific reports 20200728 1

Persistent endothelial injury promotes maladaptive responses by favoring the release of factors leading to perturbation in vascular homeostasis and tissue architecture. Caspase-3 dependent death of microvascular endothelial cells leads to the release of unique apoptotic exosome-like vesicles (ApoExo). Here, we evaluate the impact of ApoExo on endothelial gene expression and function in the context of a pro-apoptotic stimulus. Endothelial cells exposed to ApoExo differentially express genes invol ...[more]

PMID: 32724121

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Project description:Autoreactive T lymphocytes crossing the blood-brain barrier (BBB) into the central nervous system (CNS) play a crucial role in the initiation of demyelination and neurodegeneration in multiple sclerosis (MS). Recently, extracellular vesicles (EV) secreted by BBB endothelial cells (BBB-EC) have emerged as a unique form of cell-to-cell communication that contributes to cerebrovascular dysfunction. However, the precise impact of different size-based subpopulations of BBB-EC-derived EV (BBB-EV) on the early stages of MS remains unclear. Therefore, our objective was to investigate the content and function of distinct BBB-EV subpopulations in regulating BBB integrity and their role in T cell transendothelial migration, both in vitro and in vivo. Our study reveals that BBB-ECs release two distinct size based EV populations, namely small EV (sEV; 30-150 nm) and large EV (lEV; 150-300 nm), with a significantly higher secretion of sEV during inflammation. Notably, the expression patterns of cytokines and adhesion markers differ significantly between these BBB-EV subsets, indicating specific functional differences in the regulation of T cell migration. Through in vitro experiments, we demonstrate that lEV, which predominantly reflect their cellular source, play a major role in BBB integrity loss and the enhanced migration of pro-inflammatory Th1 and Th17.1 cells. Conversely, sEV appear to protect BBB function by inducing an anti-inflammatory phenotype in BBB-EC. These findings align with our in vivo data, where the administration of sEV to mice with experimental autoimmune encephalomyelitis (EAE) results in lower disease severity compared to the administration of lEV, which exacerbates disease symptoms. In conclusion, our study highlights the distinct and opposing effects of BBB-EV subpopulations on the BBB, both in vitro and in vivo. These findings underscore the need for further investigation into the diagnostic and therapeutic potential of BBB-EV in the context of MS.

Dataset Information

Apoptotic exosome-like vesicles regulate endothelial gene expression, inflammatory signaling, and function through the NF-?B signaling pathway.

Publications

Apoptotic exosome-like vesicles regulate endothelial gene expression, inflammatory signaling, and function through the NF-κB signaling pathway.

Similar Datasets

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