Chronic carbon monoxide exposure of hypoxic rats increases in vitro sensitivity of pulmonary artery smooth muscle

2003 ◽  
Vol 81 (7) ◽  
pp. 711-719 ◽  
Author(s):  
Eric Dubuis ◽  
Mathieu Gautier ◽  
Alexandre Melin ◽  
Manuel Rebocho ◽  
Catherine Girardin ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Guanylyl Cyclase ◽  
Soluble Guanylyl Cyclase ◽  
Channel Activity ◽  
Pulmonary Vasodilation ◽  
Pulmonary Artery Smooth Muscle ◽  
First Time

Exogenous carbon monoxide (CO) induces pulmonary vasodilation by acting directly on pulmonary artery (PA) smooth muscle cells. We investigated the contribution of K+ channels and soluble guanylyl cyclase to the regulation of PA tone by acute CO in chronic hypoxic rats (3 weeks at 0.5 atm (1 atm = 101.325 kPa); hypoxic) and in chronic hypoxic rats exposed to exogenous CO (3 weeks at 0.5 atm + 50 ppm CO; hypoxic-CO). Acute CO induced relaxation in PA rings from all animals. However, the amplitude of CO relaxation was significantly decreased in hypoxic rings and increased in hypoxic-CO rings. This different effect occurred with a decrease and an increase of pD2, respectively, in hypoxic and hypoxic-CO rings. We showed a positive relation between the percentage of inhibition of CO relaxation by a blocker of K+ channels and the increase of CO sensitivity. Thus, we showed for the first time that chronic hypoxia decreases acute CO sensitivity, which in contrast, increases in the presence of chronic CO. The present study provides initial evidence of a link between increased K+-channel activity and CO sensitivity.Key words: K+-channel blocker, tetraethylammonium, soluble guanylyl cyclase, gasotransmitter.

scholarly journals Regulation of soluble guanylyl cyclase-α1 expression in chronic hypoxia-induced pulmonary hypertension: role of NFATc3 and HuR

2009 ◽  
Vol 297 (3) ◽  
pp. L475-L486 ◽  
Author(s):  
Sergio de Frutos ◽  
Carlos H. Nitta ◽  
Elizabeth Caldwell ◽  
Jessica Friedman ◽  
Laura V. González Bosc
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Guanylyl Cyclase ◽  
Chronic Hypoxia ◽  
Pulmonary Arteries ◽  
Soluble Guanylyl Cyclase ◽  
Muscle Cells ◽  
Pulmonary Artery Smooth Muscle

The nitric oxide/soluble guanylyl cyclase (sGC) signal transduction pathway plays an important role in smooth muscle relaxation and phenotypic regulation. However, the transcriptional regulation of sGC gene expression is largely unknown. It has been shown that sGC expression increases in pulmonary arteries from chronic hypoxia-induced pulmonary hypertensive animals. Since the transcription factor NFATc3 is required for the upregulation of the smooth muscle hypertrophic/differentiation marker α-actin in pulmonary artery smooth muscle cells from chronically hypoxic mice, we hypothesized that NFATc3 is required for the regulation of sGC-α1 expression during chronic hypoxia. Exposure to chronic hypoxia for 2 days induced a decrease in sGC-α1 expression in mouse pulmonary arteries. This reduction was independent of NFATc3 but mediated by nuclear accumulation of the mRNA-stabilizing protein human antigen R (HuR). Consistent with our hypothesis, chronic hypoxia (21 days) upregulated pulmonary artery sGC-α1 expression, bringing it back to the level of the normoxic controls. This response was prevented in NFATc3 knockout and cyclosporin (calcineurin/NFATc inhibitor)-treated mice. Furthermore, we identified effective binding sites for NFATc in the mouse sGC-α1 promoter. Activation of NFATc3 increased sGC-α1 promoter activity in human embryonic derived kidney cells, rat aortic-derived smooth muscle cells, and human pulmonary artery smooth muscle cells. Our results suggest that NFATc3 and HuR are important regulators of sGC-α1 expression in pulmonary vascular smooth muscle cells during chronic hypoxia-induced pulmonary hypertension.

scholarly journals Extracellular vesicle cross-talk between pulmonary artery smooth muscle cells and endothelium during excessive TGF-β signalling: implications for PAH vascular remodelling

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Fernando de la Cuesta ◽  
Ilaria Passalacqua ◽  
Julie Rodor ◽  
Raghu Bhushan ◽  
Laura Denby ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Smooth Muscle Actin ◽  
Muscle Cells ◽  
Protein Markers ◽  
Vascular Remodelling ◽  
Pulmonary Artery Smooth Muscle ◽  
Tgf Β1

Abstract Background Excessive TGF-β signalling has been shown to underlie pulmonary hypertension (PAH). Human pulmonary artery smooth muscle cells (HPASMCs) can release extracellular vesicles (EVs) but their contents and significance have not yet been studied. Here, we aimed to analyse the contents and biological relevance of HPASMC-EVs and their transport to human pulmonary arterial endothelial cells (HPAECs), as well as the potential alteration of these under pathological conditions. Methods We used low-input RNA-Seq to analyse the RNA cargoes sorted into released HPASMC-EVs under basal conditions. We additionally analysed the effects of excessive TGF-β signalling, using TGF-β1 and BMP4, in the transcriptome of HPASMCs and their EVs. We then, for the first time, optimised Cre-loxP technology for its use with primary cells in vitro, directly visualising HPASMC-to-HPAEC communication and protein markers on cells taking up EVs. Furthermore we could analyse alteration of this transport with excessive TGF-β signalling, as well as by other cytokines involved in PAH: IL-1β, TNF-α and VEGFA. Results We were able to detect transcripts from 2417 genes in HPASMC-EVs. Surprisingly, among the 759 enriched in HPASMC-EVs compared to their donor cells, we found Zeb1 and 2 TGF-β superfamily ligands, GDF11 and TGF-β3. Moreover, we identified 90 genes differentially expressed in EVs from cells treated with TGF-β1 compared to EVs in basal conditions, including a subset involved in actin and ECM remodelling, among which were bHLHE40 and palladin. Finally, using Cre-loxP technology we showed cell-to-cell transfer and translation of HPASMC-EV Cre mRNA from HPASMC to HPAECs, effectively evidencing communication via EVs. Furthermore, we found increased number of smooth-muscle actin positive cells on HPAECs that took up HPASMC-EVs. The uptake and translation of mRNA was also higher in activated HPAECs, when stimulated with TGF-β1 or IL-1β. Conclusions HPASMC-EVs are enriched in RNA transcripts that encode genes that could contribute to vascular remodelling and EndoMT during development and PAH, and TGF-β1 up-regulates some that could enhance this effects. These EVs are functionally transported, increasingly taken up by activated HPAECs and contribute to EndoMT, suggesting a potential effect of HPASMC-EVs in TGF-β signalling and other related processes during PAH development.

Oxygen-induced fetal pulmonary vasodilation is mediated by intracellular calcium activation of KCa channels

2001 ◽  
Vol 281 (6) ◽  
pp. L1379-L1385 ◽  
Author(s):  
Valerie A. Porter ◽  
Michael T. Rhodes ◽  
Helen L. Reeve ◽  
David N. Cornfield
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Intracellular Calcium ◽  
Muscle Cells ◽  
Pulmonary Vasodilation ◽  
Outward Currents ◽  
Acute Increase ◽  
Pulmonary Artery Smooth Muscle ◽  
Spontaneous Transient Outward Currents

O2 sensing in fetal pulmonary artery smooth muscle is critically important in the successful transition to air breathing at birth. However, the mechanism by which the fetal pulmonary vasculature senses and responds to an acute increase in O2tension is not known. Isolated fetal pulmonary artery smooth muscle cells were kept in primary culture for 5–14 days in a hypoxic environment (20–30 mmHg). These cells showed a 25.1 ± 1.7% decrease in intracellular calcium in response to an acute increase in O2 tension. Low concentrations of caffeine (0.5 mM) and diltiazem also decreased intracellular calcium. The decrease in intracellular calcium concentration in response to increasing O2 was inhibited by iberiotoxin and ryanodine. Freshly isolated fetal pulmonary artery smooth muscle cells exhibited “spontaneous transient outward currents,” indicative of intracellular calcium spark activation of calcium-sensitive potassium channels. The frequency of spontaneous transient outward currents increased when O2 tension was increased to normoxic levels. Increasing fetal pulmonary O2 tension in acutely instrumented fetal sheep increased fetal pulmonary blood flow. Ryanodine attenuated O2-induced pulmonary vasodilation. This study demonstrates that fetal pulmonary vascular smooth muscle cells are capable of responding to an acute increase in O2tension and that this O2 response is mediated by intracellular calcium activation of calcium-sensitive potassium channels.

Calcium signalling induced by in vitro exposure to silicium dioxide nanoparticles in rat pulmonary artery smooth muscle cells

Toxicology ◽  
2017 ◽  
Vol 375 ◽  
pp. 37-47 ◽  
Author(s):  
Virginie Dubes ◽  
Thibaud Parpaite ◽  
Thomas Ducret ◽  
Jean-François Quignard ◽  
Stéphane Mornet ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Calcium Signalling ◽  
Muscle Cells ◽  
In Vitro Exposure ◽  
Pulmonary Artery Smooth Muscle ◽  
Silicium Dioxide

scholarly journals Pulmonary artery smooth muscle cell hyperproliferation and metabolic shift triggered by pulmonary overcirculation

2016 ◽  
Vol 311 (4) ◽  
pp. H944-H957 ◽  
Author(s):  
Jason Boehme ◽  
Xutong Sun ◽  
Kathryn V. Tormos ◽  
Wenhui Gong ◽  
Manuela Kellner ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Lactate Production ◽  
Pentose Phosphate ◽  
Metabolic Reprogramming ◽  
Glycolytic Flux ◽  
Pulmonary Artery Smooth Muscle

Vascular cell hyperproliferation and metabolic reprogramming contribute to the pathophysiology of pulmonary arterial hypertension (PAH). An important cause of PAH in children with congenital heart disease (CHD) is increased pulmonary blood flow (PBF). To better characterize this disease course we studied early changes in pulmonary artery smooth muscle cell (PASMC) proliferation and metabolism using a unique ovine model of pulmonary overcirculation. Consistent with PAH in adults, PASMCs derived from 4-wk-old lambs exposed to increased PBF (shunt) exhibited increased rates of proliferation. While shunt PASMCs also exhibited significant decreases in mitochondrial oxygen consumption, membrane potential, and tricarboxylic acid (TCA) cycle function, suggesting a switch to Warburg metabolism as observed in advanced PAH in adults, they unexpectedly demonstrated decreased glycolytic lactate production, likely due to enhanced flux through the pentose phosphate pathway (PPP). This may be a response to the marked increase in NADPH oxidase (Nox) activity and decreased NADPH/NADP+ ratios observed in shunt PASMCs. Consistent with these findings, pharmacological inhibition of Nox activity preferentially slowed the growth of shunt PASMCs in vitro. Our results therefore indicate that PASMC hyperproliferation is observed early in the setting of pulmonary overcirculation and is accompanied by a unique metabolic profile that is independent of HIF-1α, PDHK1, or increased glycolytic flux. Our results also suggest that Nox inhibition may help prevent pulmonary overcirculation-induced PAH in children born with CHD.

scholarly journals miR-210 has an antiapoptotic effect in pulmonary artery smooth muscle cells during hypoxia

2012 ◽  
Vol 303 (8) ◽  
pp. L682-L691 ◽  
Author(s):  
Deming Gou ◽  
Ramaswamy Ramchandran ◽  
Xiao Peng ◽  
Lijun Yao ◽  
Kang Kang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Hypoxia Inducible Factor ◽  
Cell Number ◽  
Regulation Of Transcription ◽  
Pulmonary Artery Smooth Muscle

MicroRNAs (miRNAs) were recently reported to play an important role in the pathogenesis of pulmonary arterial hypertension (PAH), but it is not clear which miRNAs are important or what pathways are involved in the process. Because hypoxia is an important stimulus for human pulmonary artery smooth muscle cell (HPASMC) proliferation and PAH, we performed miRNA microarray assays in hypoxia-treated and control HPASMC. We found that miR-210 is the predominant miRNA induced by hypoxia in HPASMC. Induction of miR-210 was also observed in whole lungs of mice with chronic hypoxia-induced PAH. We found that transcriptional induction of miR-210 in HPASMC is hypoxia-inducible factor-1α dependent. Inhibition of miR-210 in HPASMC caused a significant decrease in cell number due to increased apoptosis. We found that miR-210 appears to mediate its antiapoptotic effects via the regulation of transcription factor E2F3, a direct target of miR-210. Our results have identified miR-210 as a hypoxia-inducible miRNA both in vitro and in vivo, which inhibits pulmonary vascular smooth muscle cell apoptosis in hypoxia by specifically repressing E2F3 expression.

Sign in / Sign up

Export Citation Format

Share Document