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Open AccessArticle

c-Jun, Foxo3a, and c-Myc Transcription Factors are Key Regulators of ATP-Mediated Angiogenic Responses in Pulmonary Artery Vasa Vasorum Endothelial Cells

1
University of Colorado Denver, Department of Medicine Cardiovascular and Pulmonary Research Laboratory, Aurora, CO 80045, USA
2
University of Colorado Denver, Department of Pediatrics, Division of Critical Care Medicine, Aurora, CO 80045, USA
3
University of Colorado Denver, Department of Microbiology, Aurora, CO 80045, USA
4
Rocky Mountain Regional VA Medical Center, Aurora, CO 80045, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
† The data were Presented at the 1st European Purine Meeting, 4–6 September 2019, Santiago de Compostela, Spain.
Cells 2020, 9(2), 416; https://doi.org/10.3390/cells9020416
Received: 19 December 2019 / Revised: 6 February 2020 / Accepted: 7 February 2020 / Published: 11 February 2020
(This article belongs to the Special Issue Vascular Signalling)
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.
Keywords: vasa vasorum; angiogenesis; endothelial cells; extracellular ATP; Akt; mTOR transcription factors; c-Jun; Foxo3a; c-Myc vasa vasorum; angiogenesis; endothelial cells; extracellular ATP; Akt; mTOR transcription factors; c-Jun; Foxo3a; c-Myc
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Strassheim, D.; Karoor, V.; Nijmeh, H.; Weston, P.; Lapel, M.; Schaack, J.; Sullivan, T.; Dempsey, E.C.; Stenmark, K.R.; Gerasimovskaya, E. c-Jun, Foxo3a, and c-Myc Transcription Factors are Key Regulators of ATP-Mediated Angiogenic Responses in Pulmonary Artery Vasa Vasorum Endothelial Cells. Cells 2020, 9, 416.

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