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-κB activation. NF-κB is known to participate in endothelial dysfunction in numerous diseases. Silencing NF-κB 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-κB 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-κB activation in endothelial cells opens new avenues to prevent endothelial dysfunction.
Highlights
Persistent endothelial injury promotes maladaptive responses by favoring the release of factors leading to perturbation in vascular homeostasis and tissue architecture
Electron microscopy performed on both fractions isolated by sequential centrifugation showed distinct ultrastructural characteristics as previously d escribed[13]; apoptotic bodies being within the micron range whereas the size of apoptotic exosome-like vesicles (ApoExo) was within 30–100 nm (Fig. S2E)
We evaluated the impact of ApoExo on the expression of two endothelial markers CD31 and von Willebrand Factor
Summary
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). Our group recently showed that injury and caspase-3 dependent death of microvascular endothelial cells is pivotal to progressive renal dysfunction following IR3. We identified a novel type of extracellular vesicles (EVs), apoptotic exosome-like vesicles (ApoExo), as an additional component of the secretome of apoptotic endothelial cells produced downstream of caspase-3 activation and of potential importance in perturbing vascular homeostasis[13]. Recent work by our group shows that the RNA content of endothelial-derived ApoExo differs in quantity and quality from that of classical endothelial-derived e xosomes[21] Taken together, these recent findings support the notion that dying cells produce specific types of EVs that are aimed at alerting the immune system and triggering a pro-inflammatory response. The impact of ApoExo on endothelial homeostasis and function remains uncharacterized
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