Factor VIIa induces extracellular vesicles from the endothelium: a potential mechanism for its hemostatic effect.
Amino Acid Substitution
Animals
Endothelium, Vascular
/ metabolism
Extracellular Vesicles
/ genetics
Factor VIIa
/ pharmacology
Hemostasis
/ drug effects
Human Umbilical Vein Endothelial Cells
/ metabolism
Humans
Mice
Mice, Knockout
Mutation, Missense
Receptor, PAR-1
/ genetics
Recombinant Proteins
/ pharmacology
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
17 06 2021
17 06 2021
Historique:
received:
27
07
2020
accepted:
11
01
2021
pubmed:
4
2
2021
medline:
15
12
2021
entrez:
3
2
2021
Statut:
ppublish
Résumé
Recombinant factor FVIIa (rFVIIa) is used as a hemostatic agent to treat bleeding disorders in hemophilia patients with inhibitors and other groups of patients. Our recent studies showed that FVIIa binds endothelial cell protein C receptor (EPCR) and induces protease-activated receptor 1 (PAR1)-mediated biased signaling. The importance of FVIIa-EPCR-PAR1-mediated signaling in hemostasis is unknown. In the present study, we show that FVIIa induces the release of extracellular vesicles (EVs) from endothelial cells both in vitro and in vivo. Silencing of EPCR or PAR1 in endothelial cells blocked the FVIIa-induced generation of EVs. Consistent with these data, FVIIa treatment enhanced the release of EVs from murine brain endothelial cells isolated from wild-type (WT), EPCR-overexpressing, and PAR1-R46Q-mutant mice, but not EPCR-deficient or PAR1-R41Q-mutant mice. In vivo studies revealed that administration of FVIIa to WT, EPCR-overexpressing, and PAR1-R46Q-mutant mice, but not EPCR-deficient or PAR1-R41Q-mutant mice, increased the number of circulating EVs. EVs released in response to FVIIa treatment exhibit enhanced procoagulant activity. Infusion of FVIIa-generated EVs and not control EVs to platelet-depleted mice increased thrombin generation at the site of injury and reduced blood loss. Administration of FVIIa-generated EVs or generation of EVs endogenously by administering FVIIa augmented the hemostatic effect of FVIIa. Overall, our data reveal that FVIIa treatment, through FVIIa-EPCR-PAR1 signaling, releases EVs from the endothelium into the circulation, and these EVs contribute to the hemostatic effect of FVIIa.
Identifiants
pubmed: 33534910
pii: S0006-4971(21)00238-X
doi: 10.1182/blood.2020008417
pmc: PMC8212509
doi:
Substances chimiques
Receptor, PAR-1
0
Recombinant Proteins
0
recombinant FVIIa
AC71R787OV
Factor VIIa
EC 3.4.21.21
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3428-3442Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL107483
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL124055
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL142975
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021 by The American Society of Hematology.
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