c-Jun, Foxo3a, and c-Myc Transcription Factors are Key Regulators of ATP-Mediated Angiogenic Responses in Pulmonary Artery Vasa Vasorum Endothelial Cells.
Adenosine Triphosphate
/ metabolism
Endothelial Cells
/ metabolism
Forkhead Box Protein O3
/ genetics
Humans
Hypertension, Pulmonary
/ genetics
JNK Mitogen-Activated Protein Kinases
/ genetics
Neovascularization, Pathologic
Phosphatidylinositol 3-Kinases
/ genetics
Proto-Oncogene Proteins c-akt
/ genetics
Proto-Oncogene Proteins c-myc
/ genetics
Pulmonary Artery
/ growth & development
Receptors, Purinergic P2Y
/ genetics
Signal Transduction
/ genetics
TOR Serine-Threonine Kinases
/ genetics
Vasa Vasorum
/ growth & development
Vascular Remodeling
/ genetics
Akt
Foxo3a
angiogenesis
c-Jun
c-Myc
endothelial cells
extracellular ATP
mTOR transcription factors
vasa vasorum
Journal
Cells
ISSN: 2073-4409
Titre abrégé: Cells
Pays: Switzerland
ID NLM: 101600052
Informations de publication
Date de publication:
11 02 2020
11 02 2020
Historique:
received:
19
12
2019
revised:
06
02
2020
accepted:
07
02
2020
entrez:
15
2
2020
pubmed:
15
2
2020
medline:
27
2
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32054096
pii: cells9020416
doi: 10.3390/cells9020416
pmc: PMC7072142
pii:
doi:
Substances chimiques
FOXO3 protein, human
0
Forkhead Box Protein O3
0
MYC protein, human
0
Proto-Oncogene Proteins c-myc
0
Receptors, Purinergic P2Y
0
Adenosine Triphosphate
8L70Q75FXE
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
JNK Mitogen-Activated Protein Kinases
EC 2.7.11.24
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL086783
Pays : United States
Déclaration de conflit d'intérêts
The authors declare no conflicts of interest.
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