PMID- 23992520
OWN - NLM
STAT- MEDLINE
DCOM- 20141106
LR  - 20220318
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 170
IP  - 6
DP  - 2013 Nov
TI  - Bleomycin induces endothelial mesenchymal transition through activation of mTOR 
      pathway: a possible mechanism contributing to the sclerotherapy of venous 
      malformations.
PG  - 1210-20
LID - 10.1111/bph.12355 [doi]
AB  - BACKGROUND AND PURPOSE: Bleomycin (BLM), one of the most common sclerosants, is 
      often used to treat venous malformations (VMs). The present study was designed to 
      investigate whether endothelial mesenchymal transition (EndoMT) contributes to 
      the therapeutic effects of BLM. EXPERIMENTAL APPROACH: Endothelial and 
      mesenchymal markers of HUVECs were measured by immunofluorescence, real-time 
      quantitative PCR and Western blot analysis. Cell migration and tube formation 
      assays were performed to evaluate endothelial cell function. Slug 
      small-interfering RNA and specific inhibitors [Z-VAD-FMK for pan caspases, 
      rapamycin for mammalian target of rapamycin (mTOR)] were used to investigate the 
      mechanism. KEY RESULTS: Long term (48 h or longer) treatment with BLM 
      (0.1 mU.mL(-1) ) induced EndoMT in HUVECs, as manifested by a reduction in the 
      expression of vascular endothelial-cadherin and an up-regulation in the 
      expression of alpha-smooth muscle actin and fibroblast specific protein-1, as well as 
      activation of the transcription factor Slug. The size and protein content of the 
      transformed cells were increased. BLM also enhanced the migration of HUVECs but 
      diminished their tube formation. By employing rapamycin, we demonstrated that 
      activation of the mTOR pathway is involved in BLM-induced EndoMT in HUVECs. 
      CONCLUSIONS AND IMPLICATIONS: Our results show that a Slug-dependent EndoMT 
      process is involved in BLM-induced therapeutic effects on endothelial cells and, 
      more importantly, indicate the potential role of this process in the 
      sclerotherapy of VMs.
CI  - (c) 2013 The British Pharmacological Society.
FAU - Zhang, Wei
AU  - Zhang W
AD  - The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key 
      Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of 
      Stomatology, Wuhan University, Wuhan, China; Department of Oral & Maxillofacial - 
      Head & Neck Oncology, School and Hospital of Stomatology, Wuhan University, 
      Wuhan, China.
FAU - Chen, Gang
AU  - Chen G
FAU - Ren, Jian-Gang
AU  - Ren JG
FAU - Zhao, Yi-Fang
AU  - Zhao YF
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (SNAI1 protein, human)
RN  - 0 (Sclerosing Solutions)
RN  - 0 (Snail Family Transcription Factors)
RN  - 0 (Transcription Factors)
RN  - 11056-06-7 (Bleomycin)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Bleomycin/*pharmacology/therapeutic use
MH  - Cell Movement/drug effects
MH  - Cell Transdifferentiation/*drug effects
MH  - Human Umbilical Vein Endothelial Cells/*drug effects/physiology
MH  - Humans
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Sclerosing Solutions/*pharmacology/therapeutic use
MH  - Sclerotherapy
MH  - Sirolimus/pharmacology
MH  - Snail Family Transcription Factors
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/*metabolism
MH  - Transcription Factors/genetics/*metabolism
MH  - Vascular Diseases/drug therapy/metabolism/pathology
MH  - Veins/pathology
PMC - PMC3838696
OTO - NOTNLM
OT  - Slug
OT  - bleomycin
OT  - endothelial mesenchymal transition
OT  - mTOR
OT  - venous malformation
EDAT- 2013/09/03 06:00
MHDA- 2014/11/07 06:00
PMCR- 2014/11/01
CRDT- 2013/09/03 06:00
PHST- 2013/05/05 00:00 [received]
PHST- 2013/07/29 00:00 [revised]
PHST- 2013/08/19 00:00 [accepted]
PHST- 2013/09/03 06:00 [entrez]
PHST- 2013/09/03 06:00 [pubmed]
PHST- 2014/11/07 06:00 [medline]
PHST- 2014/11/01 00:00 [pmc-release]
AID - 10.1111/bph.12355 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2013 Nov;170(6):1210-20. doi: 10.1111/bph.12355.