Factor VIIa suppresses inflammation and barrier disruption through the release of EEVs and transfer of microRNA 10a.
Kaushik DasShiva KeshavaUsha R PendurthiL Vijaya Mohan RaoPublished in: Blood (2021)
Coagulation protease, factor VIIa (FVIIa) binds endothelial cell protein C receptor (EPCR) and induces anti-inflammatory and endothelial barrier protective responses via protease-activated receptor-1 (PAR1)-mediated biased signaling. Our recent studies showed that the FVIIa-EPCR-PAR1 axis induces the release of extracellular vesicles (EVs) from endothelial cells. The present study investigates the mechanism of FVIIa release of endothelial EVs (EEVs) and the contribution of FVIIa-released EEVs to anti-inflammatory and vascular barrier protective effects both in vitro and in vivo models. Data presented in the manuscript show multiple signaling pathways regulate FVIIa release of EVs from endothelial cells, but the ROCK-dependent pathway appears to be a major mechanism. FVIIa-released EEVs are enriched with anti-inflammatory micro RNAs, mostly miR10a. FVIIa-released EEVs were taken up readily by monocytes/macrophages and endothelial cells. The uptake of FVIIa-released EEVs by monocytes conferred anti-inflammatory phenotype to monocytes, whereas EEVs uptake by endothelial cells resulted in barrier protection. Additional studies showed that EEVs-mediated delivery of miR10a to monocytes downregulates the expression of TAK1 and activation of the NF-ĸB-mediated inflammatory pathway. In vivo studies showed that administering FVIIa-released EEVs to wild-type mice attenuated LPS-induced increased inflammatory cytokines in plasma and vascular leakage into vital tissues. The incorporation of anti-miR10a into FVIIa-released EEVs diminished the ability of FVIIa-released EEVs to confer cytoprotective effects. Administration of ROCK inhibitor Y27632 to mice, which significantly inhibits FVIIa release of EEVs into circulation, attenuates the cytoprotective effects of FVIIa. Overall, our present study reveals novel insights into how FVIIa induces cytoprotective effects and communicates with various cell types.
Keyphrases
- endothelial cells
- anti inflammatory
- lps induced
- cell proliferation
- signaling pathway
- long non coding rna
- high glucose
- oxidative stress
- wild type
- dendritic cells
- inflammatory response
- gene expression
- metabolic syndrome
- long noncoding rna
- machine learning
- immune response
- single cell
- type diabetes
- stem cells
- binding protein
- small molecule
- big data
- case control
- pi k akt
- amino acid
- artificial intelligence