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

Derek Strassheim,Evgenia Gerasimovskaya,Martin Lapel,Kurt R Stenmark,Vijaya Karoor,Hala Nijmeh,Edward C Dempsey,Philip Weston,Jerome Schaack,Timothy Sullivan

doi:10.3390/cells9020416

Derek Strassheim, Evgenia Gerasimovskaya + Show 8 more

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https://doi.org/10.3390/cells9020416

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Journal: Cells	Publication Date: Feb 11, 2020
Citations: 9	License type: CC BY 4.0

Affiliation: University of Colorado Denver

Abstract

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.

Highlights

Pathologic vascular remodeling plays a critical role in the development of cardiovascular diseases, including pulmonary hypertension (PH)
Phosphoinositide 3-kinase (PI3K) and Mammalian Target of Rapamycin (mTOR) Pathways are Involved in ATP-induced DNA Synthesis in VV endothelial cells (VVECs)
Our previous studies established the role of PI3K and Rho-ROCK pathways in ATP release and ATP-mediated proliferative responses in VVECs [18]

Summary

Introduction

Pathologic vascular remodeling plays a critical role in the development of cardiovascular diseases, including pulmonary hypertension (PH). Our previous studies revealed a marked expansion of the VV network in the adventitia of the pulmonary artery (PA) of chronically hypoxic hypertensive calves—a process that was accompanied by adventitial thickening and infiltration of circulating inflammatory cells into the arterial wall, implicating the VV in pathologic vascular remodeling in PH [3,8,9,10]. It is likely important in pathological vascular remodeling, little is known about the molecular mechanisms underlying these pathological events. Under pathological conditions, including hypoxia and inflammation, ATP is released from vascular and blood cells and mediates its effect by acting on P2Y (G protein-coupled) and P2X (metabotropic) purinergic receptors [11,12,13,14,15,16,17]

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