PMID- 31259295
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201001
IS  - 2512-9465 (Electronic)
IS  - 2567-3459 (Print)
IS  - 2512-9465 (Linking)
VI  - 3
IP  - 2
DP  - 2019 Apr
TI  - The Ratio of Factor VIIa:Tissue Factor Content within Microvesicles Determines 
      the Differential Influence on Endothelial Cells.
PG  - e132-e145
LID - 10.1055/s-0039-1688934 [doi]
AB  - Tissue factor (TF)-positive microvesicles from various sources can promote 
      cellular proliferation or alternatively induce apoptosis, but the determining 
      factors are unknown. In this study the hypothesis that the ratio of fVIIa:TF 
      within microvesicles determines this outcome was examined. Microvesicles were 
      isolated from HepG2, BxPC-3, 786-O, MDA-MB-231, and MCF-7 cell lines and 
      microvesicle-associated fVIIa and TF antigen and activity levels were measured. 
      Human coronary artery endothelial cells (HCAECs) were incubated with these 
      purified microvesicles, or with combinations of fVIIa-recombinant TF, and cell 
      proliferation/apoptosis was measured. Additionally, by expressing mCherry-PAR2 on 
      HCAEC surface, PAR2 activation was quantified. Finally, the activation of PAR2 on 
      HCAEC or the activities of TF and fVIIa in microvesicles were blocked prior to 
      addition of microvesicles to cells. The purified microvesicles exhibited a range 
      of fVIIa:TF ratios with HepG2 and 786-O cells having the highest (54:1) and 
      lowest (10:1) ratios, respectively. The reversal from proapoptotic to 
      proliferative was estimated to occur at a fVIIa:TF molar ratio of 15:1, but HCAEC 
      could not be rescued at higher TF concentrations. The purified microvesicles 
      induced HCAEC proliferation or apoptosis according to this ruling. Blocking PAR2 
      activation on HCAEC, or inhibiting fVIIa or TF-procoagulant function on 
      microvesicles prevented the influence on HCAEC. Finally, incubation of HCAEC with 
      recombinant TF resulted in increased surface exposure of fVII. The induction of 
      cell proliferation or apoptosis by TF-positive microvesicles is dependent on the 
      ratio of fVIIa:TF and involves the activation of PAR2. At lower TF 
      concentrations, fVIIa can counteract the proapoptotic stimulus and induce 
      proliferation.
FAU - Madkhali, Yahya
AU  - Madkhali Y
AD  - Department of Biomedical Sciences, University of Hull, Hull, United Kingdom.
AD  - Department of Medical Laboratories, College of Applied Medical Sciences, Majmaah 
      University, KSA, Al Majmaah, Saudi Arabia.
FAU - Featherby, Sophie
AU  - Featherby S
AD  - Department of Biomedical Sciences, University of Hull, Hull, United Kingdom.
FAU - Collier, Mary E
AU  - Collier ME
AD  - Department of Cardiovascular Sciences, University of Leicester, Glenfield General 
      Hospital, Leicester, United Kingdom.
FAU - Maraveyas, Anthony
AU  - Maraveyas A
AD  - Division of Cancer-Hull York Medical School, University of Hull, Hull, United 
      Kingdom.
FAU - Greenman, John
AU  - Greenman J
AD  - Department of Biomedical Sciences, University of Hull, Hull, United Kingdom.
FAU - Ettelaie, Camille
AU  - Ettelaie C
AUID- ORCID: 0000-0002-6121-5262
AD  - Department of Biomedical Sciences, University of Hull, Hull, United Kingdom.
LA  - eng
PT  - Journal Article
DEP - 20190515
PL  - Germany
TA  - TH Open
JT  - TH open : companion journal to thrombosis and haemostasis
JID - 101715740
PMC - PMC6598090
OTO - NOTNLM
OT  - apoptosis
OT  - cell proliferation
OT  - factor VIIa
OT  - microvesicles
OT  - protease-activated receptor-2
OT  - tissue factor
COIS- Conflict of Interest A.M. reports support from and is a consultant and scientific 
      advisor for Bayer. The other authors declare no conflict of interest.
EDAT- 2019/07/02 06:00
MHDA- 2019/07/02 06:01
PMCR- 2019/05/15
CRDT- 2019/07/02 06:00
PHST- 2018/12/31 00:00 [received]
PHST- 2019/04/10 00:00 [accepted]
PHST- 2019/07/02 06:00 [entrez]
PHST- 2019/07/02 06:00 [pubmed]
PHST- 2019/07/02 06:01 [medline]
PHST- 2019/05/15 00:00 [pmc-release]
AID - 190014 [pii]
AID - 10.1055/s-0039-1688934 [doi]
PST - epublish
SO  - TH Open. 2019 May 15;3(2):e132-e145. doi: 10.1055/s-0039-1688934. eCollection 
      2019 Apr.