Role of Purine-Converting Ecto-Enzymes in Angiogenic Phenotype of Pulmonary Artery Adventitial Vasa Vasorum Endothelial Cells of Chronically Hypoxic Calves

2010 ◽  
pp. 73-93 ◽  
Author(s):  
Evgenia V. Gerasimovskaya ◽  
Kurt R. Stenmark ◽  
Gennady G. Yegutkin
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Artery ◽  
Vasa Vasorum

scholarly journals 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 ◽  
Vol 9 (2) ◽  
pp. 416
Author(s):  
Derek Strassheim ◽  
Vijaya Karoor ◽  
Hala Nijmeh ◽  
Philip Weston ◽  
Martin Lapel ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcription Factors ◽  
Pulmonary Artery ◽  
Molecular Mechanisms ◽  
Cell Cycle Control ◽  
Critical Role ◽  
Mammalian Target Of Rapamycin ◽  
Vasa Vasorum ◽  
Angiogenic Factor ◽  
Angiogenic Genes

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.

scholarly journals P2Y1 and P2Y13 purinergic receptors mediate Ca2+ signaling and proliferative responses in pulmonary artery vasa vasorum endothelial cells

2011 ◽  
Vol 300 (2) ◽  
pp. C266-C275 ◽  
Author(s):  
Taras Lyubchenko ◽  
Heather Woodward ◽  
Kristopher D. Veo ◽  
Nana Burns ◽  
Hala Nijmeh ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Artery ◽  
Purinergic Receptors ◽  
Purinergic Receptor ◽  
Extracellular Atp ◽  
Vasa Vasorum ◽  
Receptor Subtypes ◽  
Extracellular Nucleotide ◽  
Selective Antagonist ◽  
Intracellular Ca

Extracellular ATP and ADP have been shown to exhibit potent angiogenic effects on pulmonary artery adventitial vasa vasorum endothelial cells (VVEC). However, the molecular signaling mechanisms of extracellular nucleotide-mediated angiogenesis remain not fully elucidated. Since elevation of intracellular Ca2+ concentration ([Ca2+]i) is required for cell proliferation and occurs in response to extracellular nucleotides, this study was undertaken to delineate the purinergic receptor subtypes involved in Ca2+ signaling and extracellular nucleotide-mediated mitogenic responses in VVEC. Our data indicate that stimulation of VVEC with extracellular ATP resulted in the elevation of [Ca2+]i via Ca2+ influx through plasma membrane channels as well as Ca2+ mobilization from intracellular stores. Moreover, extracellular ATP induced simultaneous Ca2+ responses in both cytosolic and nuclear compartments. An increase in [Ca2+]i was observed in response to a wide range of purinergic receptor agonists, including ATP, ADP, ATPγS, ADPβS, UTP, UDP, 2-methylthio-ATP (MeSATP), 2-methylthio-ADP (MeSADP), and BzATP, but not adenosine, AMP, diadenosine tetraphosphate, αβMeATP, and βγMeATP. Using RT-PCR, we identified mRNA for the P2Y1, P2Y2, P2Y4, P2Y13, P2Y14, P2X2, P2X5, P2X7, A1, A2b, and A3 purinergic receptors in VVEC. Preincubation of VVEC with the P2Y1 selective antagonist MRS2179 and the P2Y13 selective antagonist MRS2211, as well as with pertussis toxin, attenuated at varying degrees agonist-induced intracellular Ca2+ responses and activation of ERK1/2, Akt, and S6 ribosomal protein, indicating that P2Y1 and P2Y13 receptors play a major role in VVEC growth responses. Considering the broad physiological implications of purinergic signaling in the regulation of angiogenesis and vascular homeostasis, our findings suggest that P2Y1 and P2Y13 receptors may represent novel and specific targets for treatment of pathological vascular remodeling involving vasa vasorum expansion.

scholarly journals Pulmonary Artery Adventitial Fibroblasts Cooperate with Vasa Vasorum Endothelial Cells to Regulate Vasa Vasorum Neovascularization

2006 ◽  
Vol 168 (6) ◽  
pp. 1793-1807 ◽  
Author(s):  
Neil J. Davie ◽  
Evgenia V. Gerasimovskaya ◽  
Stephen E. Hofmeister ◽  
Aaron P. Richman ◽  
Peter L. Jones ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Artery ◽  
Vasa Vasorum ◽  
Adventitial Fibroblasts

scholarly journals Role of 12-lipoxygenase in hypoxia-induced rat pulmonary artery smooth muscle cell proliferation

2006 ◽  
Vol 290 (2) ◽  
pp. L367-L374 ◽  
Author(s):  
Ioana R. Preston ◽  
Nicholas S. Hill ◽  
Rod R. Warburton ◽  
Barry L. Fanburg
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Protein Expression ◽  
Pulmonary Arteries ◽  
Mek Inhibitor ◽  
Gene And Protein Expression ◽  
12 Lipoxygenase

The 12-lipoxygenase (12-LO) pathway of arachidonic acid metabolism stimulates cell growth and metastasis of various cancer cells and the 12-LO metabolite, 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], enhances proliferation of aortic smooth muscle cells (SMCs). However, pulmonary vascular effects of 12-LO have not been previously studied. We sought evidence for a role of 12-LO and 12(S)-HETE in the development of hypoxia-induced pulmonary hypertension. We found that 12-LO gene and protein expression is elevated in lung homogenates of rats exposed to chronic hypoxia. Immunohistochemical staining with a 12-LO antibody revealed intense staining in endothelial cells of large pulmonary arteries, SMCs (and possibly endothelial cells) of medium and small-size pulmonary arteries and in alveolar walls of hypoxic lungs. 12-LO protein expression was increased in hypoxic cultured rat pulmonary artery SMCs. 12(S)-HETE at concentrations as low as 10−5 μM stimulated proliferation of pulmonary artery SMCs. 12(S)-HETE induced ERK 1/ERK 2 phosphorylation but had no effect on p38 kinase expression as assessed by Western blotting. 12(S)-HETE-stimulated SMC proliferation was blocked by the MEK inhibitor PD-98059, but not by the p38 MAPK inhibitor SB-202190. Hypoxia (3%)-stimulated pulmonary artery SMC proliferation was blocked by both U0126, a MEK inhibitor, and baicalein, an inhibitor of 12-LO. We conclude that 12-LO and its product, 12(S)-HETE, are important intermediates in hypoxia-induced pulmonary artery SMC proliferation and may participate in hypoxia-induced pulmonary hypertension.

Role of the Na/H antiport in pH-dependent cell death in pulmonary artery endothelial cells

2000 ◽  
Vol 278 (3) ◽  
pp. L536-L544 ◽  
Author(s):  
M. Cutaia ◽  
K. Tollefson ◽  
J. Kroczynski ◽  
N. Parks ◽  
S. Rounds
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Pulmonary Artery ◽  
Phorbol Ester ◽  
Atp Depletion ◽  
Live Cells ◽  
Cell Death Pathway ◽  
Ph Dependent ◽  
Human Pulmonary Artery

We investigated the role of intracellular pH (pHi) and Na/H exchange in cell death in human pulmonary artery endothelial cells (HPAEC) following a metabolic insult (inhibition-oxidative phosphorylation, glycolysis). Metabolic inhibition in medium at pH 7.4 decreased viability (0–15% live cells) over 6 h. Cell death was attenuated by maneuvers that decreased pHi and inhibited Na/H exchange (acidosis, Na/H antiport inhibitors). In contrast, cell death was potentiated by maneuvers that elevated pHi or increased Na/H exchange (monensin, phorbol ester treatment) before the insult. HPAEC demonstrated a biphasic pHi response following a metabolic insult. An initial decrease in pHi was followed by a return to baseline over 60 min. Maneuvers that protected HPAEC and inhibited Na/H exchange (acidosis, Na+-free medium, antiport inhibitors) altered this pattern. pHi decreased, but no recovery was observed, suggesting that the return of pHi to normal was mediated by antiport activation. Although Na/H antiport activity was reduced (55–60% of control) following a metabolic insult, the cells still demonstrated active Na/H exchange despite significant ATP depletion. Phorbol ester pretreatment, which potentiated cell death, increased Na/H antiport activity above the level observed in monolayers subjected to a metabolic insult alone. These results demonstrate that HPAEC undergo a pH-dependent loss of viability linked to active Na/H exchange following a metabolic insult. Potentiation of cell death with phorbol ester treatment suggests that this cell death pathway involves protein kinase C-mediated phosphorylation events.

Hypoxia-induced pulmonary artery adventitial remodeling and neovascularization: contribution of progenitor cells

2004 ◽  
Vol 286 (4) ◽  
pp. L668-L678 ◽  
Author(s):  
Neil J. Davie ◽  
Joseph T. Crossno ◽  
Maria G. Frid ◽  
Stephen E. Hofmeister ◽  
John T. Reeves ◽  
...  
Keyword(s):  
Pulmonary Artery ◽  
Progenitor Cells ◽  
Vessel Wall ◽  
Mononuclear Cells ◽  
Flow Cytometric Analysis ◽  
Vasa Vasorum ◽  
Tyrosine Kinase Receptor ◽  
Wall Thickening ◽  
Factor C

Information is rapidly emerging regarding the important role of the arterial vasa vasorum in a variety of systemic vascular diseases. In addition, increasing evidence suggests that progenitor cells of bone marrow (BM) origin may contribute to postnatal neovascularization and/or vascular wall thickening that is characteristic in some forms of systemic vascular disease. Little is known regarding postnatal vasa formation and the role of BM-derived progenitor cells in the setting of pulmonary hypertension (PH). We sought to determine the effects of chronic hypoxia on the density of vasa vasorum in the pulmonary artery and to evaluate if BM-derived progenitor cells contribute to the increased vessel wall mass in a bovine model of hypoxia-induced PH. Quantitative morphometric analyses of lung tissue from normoxic and hypoxic calves revealed that hypoxia results in a dramatic expansion of the pulmonary artery adventitial vasa vasorum. Flow cytometric analysis demonstrated that cells expressing the transmembrane tyrosine kinase receptor for stem cell factor, c-kit, are mobilized from the BM in the circulation in response to hypoxia. Immunohistochemistry revealed an increase in the expression of c- kit+ cells together with vascular endothelial growth factor, fibronectin, and thrombin in the hypoxia-induced remodeled pulmonary artery vessel wall. Circulating mononuclear cells isolated from neonatal calves exposed to hypoxia were found to differentiate into endothelial and smooth muscle cell phenotypes depending on culture conditions. From these observations, we suggest that the vasa vasorum and circulating progenitor cells could be involved in vessel wall thickening in the setting of hypoxia-induced PH.

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