PMID- 28775072
OWN - NLM
STAT- MEDLINE
DCOM- 20171010
LR  - 20181113
IS  - 1524-4636 (Electronic)
IS  - 1079-5642 (Print)
IS  - 1079-5642 (Linking)
VI  - 37
IP  - 10
DP  - 2017 Oct
TI  - Lmo2 (LIM-Domain-Only 2) Modulates Sphk1 (Sphingosine Kinase) and Promotes 
      Endothelial Cell Migration.
PG  - 1860-1868
LID - 10.1161/ATVBAHA.117.309609 [doi]
AB  - OBJECTIVE: Lmo (LIM-domain-only)2 transcription factor is involved in 
      hematopoiesis and vascular remodeling. Sphk (sphingosine kinase)1 phosphorylates 
      sphingosine to S1P (sphingosine-1-phosphate). We hypothesized that Lmo2 regulates 
      Sphk1 to promote endothelial cell (EC) migration and vascular development. 
      APPROACH AND RESULTS: Lmo2 and Sphk1 knockdown (KD) were performed in 
      Tg(fli1:EGFP) (y1) zebrafish and in human umbilical vein EC. Rescue of phenotypes 
      or overexpression of these factors were achieved using mRNA encoding Lmo2 or 
      Sphk1. EC proliferation in vivo was assessed by BrdU (bromodeoxyuridine) 
      immunostaining and fluorescence-activated cell sorter analysis of dissociated 
      Tg(fli1:EGFP) (y1) embryos. Cell migration was assessed by scratch assay in human 
      umbilical vein EC and mouse aortic rings. Lmo2 interactions with Sphk1 promoter 
      were assessed by ChIP-PCR (chromatin immunoprecipitation-polymerase chain 
      reaction). Lmo2 or Sphk1 KD reduced number and length of intersegmental vessels. 
      There was no reduction in the numbers of GFP(+) (green fluorescent protein) ECs 
      after Lmo2 KD. However, reduced numbers of BrdU(+)GFP(+) nuclei were observed 
      along the dysmorphic intersegmental vessels, accumulating instead at the 
      sprouting origin of the intersegmental vessels. This anomaly was likely because 
      of impaired EC migration, which was confirmed in migration assays using Lmo2 KD 
      human umbilical vein ECs and mouse aortic rings. Both in vivo and in vitro, Lmo2 
      KD reduced Sphk1 gene expression, associated with less Lmo2 binding to the Sphk1 
      promoter as assessed by ChIP-PCR. Sphk1 mRNA rescued the Lmo2 KD phenotype. 
      CONCLUSIONS: Our data showed that Lmo2 is necessary for Sphk1 gene expression in 
      ECs. Lmo2 KD reduced Lmo2-Sphk1 gene interaction, impaired intersegmental vessels 
      formation, and reduced cell migration. We identified for the first time Sphk1 as 
      downstream effector of Lmo2.
CI  - (c) 2017 American Heart Association, Inc.
FAU - Matrone, Gianfranco
AU  - Matrone G
AD  - From the Department of Cardiovascular Sciences, Houston Methodist Research 
      Institute, TX.
FAU - Meng, Shu
AU  - Meng S
AD  - From the Department of Cardiovascular Sciences, Houston Methodist Research 
      Institute, TX.
FAU - Gu, Qilin
AU  - Gu Q
AD  - From the Department of Cardiovascular Sciences, Houston Methodist Research 
      Institute, TX.
FAU - Lv, Jie
AU  - Lv J
AD  - From the Department of Cardiovascular Sciences, Houston Methodist Research 
      Institute, TX.
FAU - Fang, Longhou
AU  - Fang L
AD  - From the Department of Cardiovascular Sciences, Houston Methodist Research 
      Institute, TX.
FAU - Chen, Kaifu
AU  - Chen K
AD  - From the Department of Cardiovascular Sciences, Houston Methodist Research 
      Institute, TX.
FAU - Cooke, John P
AU  - Cooke JP
AD  - From the Department of Cardiovascular Sciences, Houston Methodist Research 
      Institute, TX. jpcooke@houstonmethodist.org.
LA  - eng
GR  - RC2 HL103400/HL/NHLBI NIH HHS/United States
GR  - U01 HL100397/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20170803
PL  - United States
TA  - Arterioscler Thromb Vasc Biol
JT  - Arteriosclerosis, thrombosis, and vascular biology
JID - 9505803
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (LIM Domain Proteins)
RN  - 0 (LMO2 protein, human)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Transcription Factors)
RN  - 0 (Zebrafish Proteins)
RN  - 0 (lmo2 protein, zebrafish)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.- (sphingosine kinase)
SB  - IM
CIN - Arterioscler Thromb Vasc Biol. 2017 Oct;37(10):1806-1808. PMID: 28954807
MH  - Adaptor Proteins, Signal Transducing/*metabolism
MH  - Animals
MH  - *Cell Movement
MH  - Cell Proliferation
MH  - Endothelial Cells/cytology/*metabolism
MH  - Gene Expression
MH  - Human Umbilical Vein Endothelial Cells/metabolism
MH  - Humans
MH  - LIM Domain Proteins/*metabolism
MH  - *Neovascularization, Physiologic
MH  - Phosphotransferases (Alcohol Group Acceptor)/genetics/*metabolism
MH  - Proto-Oncogene Proteins/*metabolism
MH  - Transcription Factors/*metabolism
MH  - Zebrafish
MH  - Zebrafish Proteins/*metabolism
PMC - PMC5637529
MID - NIHMS894844
OTO - NOTNLM
OT  - Lmo2
OT  - Sphk1
OT  - endothelium
OT  - hematopoiesis
OT  - migration
EDAT- 2017/08/05 06:00
MHDA- 2017/10/11 06:00
PMCR- 2018/10/01
CRDT- 2017/08/05 06:00
PHST- 2017/04/01 00:00 [received]
PHST- 2017/07/10 00:00 [accepted]
PHST- 2017/08/05 06:00 [pubmed]
PHST- 2017/10/11 06:00 [medline]
PHST- 2017/08/05 06:00 [entrez]
PHST- 2018/10/01 00:00 [pmc-release]
AID - ATVBAHA.117.309609 [pii]
AID - 10.1161/ATVBAHA.117.309609 [doi]
PST - ppublish
SO  - Arterioscler Thromb Vasc Biol. 2017 Oct;37(10):1860-1868. doi: 
      10.1161/ATVBAHA.117.309609. Epub 2017 Aug 3.