PMID- 32054096
OWN - NLM
STAT- MEDLINE
DCOM- 20210226
LR  - 20211204
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 9
IP  - 2
DP  - 2020 Feb 11
TI  - c-Jun, Foxo3a, and c-Myc Transcription Factors are Key Regulators of ATP-Mediated 
      Angiogenic Responses in Pulmonary Artery Vasa Vasorum Endothelial Cells.
LID - 10.3390/cells9020416 [doi]
LID - 416
AB  - Angiogenic vasa vasorum (VV) expansion plays an essential role in the 
      pathogenesis of hypoxia-induced pulmonary hypertension (PH), a cardiovascular 
      disease. We previously showed that extracellular ATP released under hypoxic 
      conditions is an autocrine/paracrine, the angiogenic factor for pulmonary artery 
      (PA) VV endothelial cells (VVECs), acting via P2Y purinergic receptors (P2YR) and 
      the Phosphoinositide 3-kinase (PI3K)-Akt-Mammalian Target of Rapamycin (mTOR) 
      signaling. To further elucidate the molecular mechanisms of ATP-mediated VV 
      angiogenesis, we determined the profile of ATP-inducible transcription factors 
      (TFs) in VVECs using a TranSignal protein/DNA array. C-Jun, c-Myc, and Foxo3 were 
      found to be upregulated in most VVEC populations and formed nodes connecting 
      several signaling networks. siRNA-mediated knockdown (KD) of these TFs revealed 
      their critical role in ATP-induced VVEC angiogenic responses and the regulation 
      of downstream targets involved in tissue remodeling, cell cycle control, 
      expression of endothelial markers, cell adhesion, and junction proteins. Our 
      results showed that c-Jun was required for the expression of ATP-stimulated 
      angiogenic genes, c-Myc was repressive to anti-angiogenic genes, and Foxo3a 
      predominantly controlled the expression of anti-apoptotic and junctional 
      proteins. The findings from our study suggest that pharmacological targeting of 
      the components of P2YR-PI3K-Akt-mTOR axis and specific TFs reduced ATP-mediated 
      VVEC angiogenic response and may have a potential translational significance in 
      attenuating pathological vascular remodeling.
FAU - Strassheim, Derek
AU  - Strassheim D
AD  - University of Colorado Denver, Department of Medicine Cardiovascular and 
      Pulmonary Research Laboratory, Aurora, CO 80045, USA.
FAU - Karoor, Vijaya
AU  - Karoor V
AD  - University of Colorado Denver, Department of Medicine Cardiovascular and 
      Pulmonary Research Laboratory, Aurora, CO 80045, USA.
FAU - Nijmeh, Hala
AU  - Nijmeh H
AD  - University of Colorado Denver, Department of Pediatrics, Division of Critical 
      Care Medicine, Aurora, CO 80045, USA.
FAU - Weston, Philip
AU  - Weston P
AD  - University of Colorado Denver, Department of Pediatrics, Division of Critical 
      Care Medicine, Aurora, CO 80045, USA.
FAU - Lapel, Martin
AU  - Lapel M
AD  - University of Colorado Denver, Department of Pediatrics, Division of Critical 
      Care Medicine, Aurora, CO 80045, USA.
FAU - Schaack, Jerome
AU  - Schaack J
AD  - University of Colorado Denver, Department of Microbiology, Aurora, CO 80045, USA.
FAU - Sullivan, Timothy
AU  - Sullivan T
AD  - University of Colorado Denver, Department of Medicine Cardiovascular and 
      Pulmonary Research Laboratory, Aurora, CO 80045, USA.
FAU - Dempsey, Edward C
AU  - Dempsey EC
AD  - University of Colorado Denver, Department of Medicine Cardiovascular and 
      Pulmonary Research Laboratory, Aurora, CO 80045, USA.
AD  - Rocky Mountain Regional VA Medical Center, Aurora, CO 80045, USA.
FAU - Stenmark, Kurt R
AU  - Stenmark KR
AD  - University of Colorado Denver, Department of Medicine Cardiovascular and 
      Pulmonary Research Laboratory, Aurora, CO 80045, USA.
AD  - University of Colorado Denver, Department of Pediatrics, Division of Critical 
      Care Medicine, Aurora, CO 80045, USA.
FAU - Gerasimovskaya, Evgenia
AU  - Gerasimovskaya E
AD  - University of Colorado Denver, Department of Medicine Cardiovascular and 
      Pulmonary Research Laboratory, Aurora, CO 80045, USA.
AD  - University of Colorado Denver, Department of Pediatrics, Division of Critical 
      Care Medicine, Aurora, CO 80045, USA.
LA  - eng
GR  - R01 HL086783/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20200211
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (FOXO3 protein, human)
RN  - 0 (Forkhead Box Protein O3)
RN  - 0 (MYC protein, human)
RN  - 0 (Proto-Oncogene Proteins c-myc)
RN  - 0 (Receptors, Purinergic P2Y)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Endothelial Cells/metabolism/pathology
MH  - Forkhead Box Protein O3/*genetics
MH  - Humans
MH  - Hypertension, Pulmonary/*genetics/pathology
MH  - JNK Mitogen-Activated Protein Kinases/*genetics
MH  - Neovascularization, Pathologic
MH  - Phosphatidylinositol 3-Kinases/genetics
MH  - Proto-Oncogene Proteins c-akt/genetics
MH  - Proto-Oncogene Proteins c-myc/*genetics
MH  - Pulmonary Artery/growth & development/metabolism/pathology
MH  - Receptors, Purinergic P2Y/genetics
MH  - Signal Transduction/genetics
MH  - TOR Serine-Threonine Kinases/genetics
MH  - Vasa Vasorum/*growth & development/pathology
MH  - Vascular Remodeling/genetics
PMC - PMC7072142
OTO - NOTNLM
OT  - Akt
OT  - Foxo3a
OT  - angiogenesis
OT  - c-Jun
OT  - c-Myc
OT  - endothelial cells
OT  - extracellular ATP
OT  - mTOR transcription factors
OT  - vasa vasorum
COIS- The authors declare no conflicts of interest.
EDAT- 2020/02/15 06:00
MHDA- 2021/02/27 06:00
PMCR- 2020/02/01
CRDT- 2020/02/15 06:00
PHST- 2019/12/19 00:00 [received]
PHST- 2020/02/06 00:00 [revised]
PHST- 2020/02/07 00:00 [accepted]
PHST- 2020/02/15 06:00 [entrez]
PHST- 2020/02/15 06:00 [pubmed]
PHST- 2021/02/27 06:00 [medline]
PHST- 2020/02/01 00:00 [pmc-release]
AID - cells9020416 [pii]
AID - cells-09-00416 [pii]
AID - 10.3390/cells9020416 [doi]
PST - epublish
SO  - Cells. 2020 Feb 11;9(2):416. doi: 10.3390/cells9020416.