Pulmonary arterial smooth muscle contractility in hypoxia-induced pulmonary hypertension

1994 ◽  
Vol 77 (1) ◽  
pp. 406-414 ◽  
Author(s):  
S. L. Griffith ◽  
R. A. Rhoades ◽  
C. S. Packer
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Chronic Hypoxia ◽  
Morphological Changes ◽  
Pulmonary Vasculature ◽  
Sprague Dawley ◽  
Muscle Contractility ◽  
Smooth Muscle Contractility ◽  
Cross Sectional ◽  
Pulmonary Arterial

The highly compliant low-resistance pulmonary vasculature is markedly altered with chronic hypoxia. Remodeling in response to hypoxia and/or hypertension involves hypertrophy and hyperplasia of smooth muscle and excessive deposition of connective tissue that likely contributes to the maintenance or exasperates the already elevated pulmonary arterial (PA) pressure. The purpose of this study was to investigate the effect of chronic hypoxia on the contractile properties of PA smooth muscle. Isometric and isotonic experiments were performed on excised PA rings from pulmonary hypertensive (induced by 14 days of hypoxia) Sprague-Dawley rats. A doubling of the vessel wall thickness occurred during the development of hypoxia-induced pulmonary hypertension. Functionally, there was a decrease in isometric stress (force to cross-sectional area ratio). No difference was detected in the velocity of shortening or in total shortening ability. This study provides evidence that, in addition to the morphological changes, changes in PA smooth muscle contractility also appear to play a role in the development and/or maintenance of hypoxia-induced pulmonary hypertension.

Chronic hypoxia elevates intracellular pH and activates Na+/H+ exchange in pulmonary arterial smooth muscle cells

2005 ◽  
Vol 289 (5) ◽  
pp. L867-L874 ◽  
Author(s):  
Eon J. Rios ◽  
Michele Fallon ◽  
Jian Wang ◽  
Larissa A. Shimoda
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Intracellular Ph ◽  
Chronic Hypoxia ◽  
Rt Pcr ◽  
Arterial Smooth Muscle ◽  
Gene And Protein Expression ◽  
Pulmonary Arterial ◽  
Arterial Smooth Muscle Cells ◽  
Pulmonary Arterial Smooth Muscle

Chronic hypoxia (CH), caused by many lung diseases, results in pulmonary hypertension due, in part, to increased muscularity of small pulmonary vessels. Pulmonary arterial smooth muscle cell (PASMC) proliferation in response to growth factors requires increased intracellular pH (pHi) mediated by activation of Na+/H+ exchange (NHE); however, the effect of CH on PASMC pHi homeostasis is unknown. Thus we measured basal pHi and NHE activity and expression in PASMCs isolated from mice exposed to normoxia or CH (3 wk/10% O2). pHi was measured using the pH-sensitive fluorescent dye BCECF-AM. NHE activity was determined from Na+-dependent recovery from NH4-induced acidosis, and NHE expression was determined by RT-PCR and immunoblot. PASMCs from chronically hypoxic mice exhibited elevated basal pHi and increased NHE activity. NHE1 was the predominate isoform present in mouse PASMCs, and both gene and protein expression of NHE1 was increased following exposure to CH. Our findings indicate that exposure to CH caused increased pHi, NHE activity, and NHE1 expression, changes that may contribute to the development of pulmonary hypertension, in part, via pH-dependent induction of PASMC proliferation.

scholarly journals Chronic hypoxia limits H2O2-induced inhibition of ASIC1-dependent store-operated calcium entry in pulmonary arterial smooth muscle

2014 ◽  
Vol 307 (5) ◽  
pp. L419-L430 ◽  
Author(s):  
Danielle R. Plomaritas ◽  
Lindsay M. Herbert ◽  
Tracylyn R. Yellowhair ◽  
Thomas C. Resta ◽  
Laura V. Gonzalez Bosc ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Chronic Hypoxia ◽  
Inhibitory Effect ◽  
Alternative Mechanism ◽  
Arterial Smooth Muscle ◽  
Hypoxic Pulmonary Hypertension ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle ◽  
Expression And Activity

Our laboratory shows that acid-sensing ion channel 1 (ASIC1) contributes to the development of hypoxic pulmonary hypertension by augmenting store-operated Ca2+ entry (SOCE) that is associated with enhanced agonist-induced vasoconstriction and arterial remodeling. However, this enhanced Ca2+ influx following chronic hypoxia (CH) is not dependent on an increased ASIC1 protein expression in pulmonary arterial smooth muscle cells (PASMC). It is well documented that hypoxic pulmonary hypertension is associated with changes in redox potential and reactive oxygen species homeostasis. ASIC1 is a redox-sensitive channel showing increased activity in response to reducing agents, representing an alternative mechanism of regulation. We hypothesize that the enhanced SOCE following CH results from removal of an inhibitory effect of hydrogen peroxide (H2O2) on ASIC1. We found that CH increased PASMC superoxide (O2·−) and decreased rat pulmonary arterial H2O2 levels. This decrease in H2O2 is a result of decreased Cu/Zn superoxide dismutase expression and activity, as well as increased glutathione peroxidase (GPx) expression and activity following CH. Whereas H2O2 inhibited ASIC1-dependent SOCE in PASMC from control and CH animals, addition of catalase augmented ASIC1-mediated SOCE in PASMC from control rats but had no further effect in PASMC from CH rats. These data suggest that, under control conditions, H2O2 inhibits ASIC1-dependent SOCE. Furthermore, H2O2 levels are decreased following CH as a result of diminished dismutation of O2·− and increased H2O2 catalysis through GPx-1, leading to augmented ASIC1-dependent SOCE.

scholarly journals Pneumonectomy combined with SU5416 induces severe pulmonary hypertension in rats

2016 ◽  
Vol 310 (11) ◽  
pp. L1088-L1097 ◽  
Author(s):  
C. M. Happé ◽  
M. A. de Raaf ◽  
N. Rol ◽  
I. Schalij ◽  
A. Vonk-Noordegraaf ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Systolic Pressure ◽  
Endothelial Cell Proliferation ◽  
Pulmonary Vasculature ◽  
Hypoxic Exposure ◽  
Sprague Dawley ◽  
Pulmonary Arterial ◽  
Severe Pulmonary Arterial Hypertension

The SU5416 + hypoxia (SuHx) rat model is a commonly used model of severe pulmonary arterial hypertension. While it is known that exposure to hypoxia can be replaced by another type of hit (e.g., ovalbumin sensitization) it is unknown whether abnormal pulmonary blood flow (PBF), which has long been known to invoke pathological changes in the pulmonary vasculature, can replace the hypoxic exposure. Here we studied if a combination of SU5416 administration combined with pneumonectomy (PNx), to induce abnormal PBF in the contralateral lung, is sufficient to induce severe pulmonary arterial hypertension (PAH) in rats. Sprague Dawley rats were subjected to SuPNx protocol (SU5416 + combined with left pneumonectomy) or standard SuHx protocol, and comparisons between models were made at week 2 and 6 postinitiation. Both SuHx and SuPNx models displayed extensive obliterative vascular remodeling leading to an increased right ventricular systolic pressure at week 6. Similar inflammatory response in the lung vasculature of both models was observed alongside increased endothelial cell proliferation and apoptosis. This study describes the SuPNx model, which features severe PAH at 6 wk and could serve as an alternative to the SuHx model. Our study, together with previous studies on experimental models of pulmonary hypertension, shows that the typical histopathological findings of PAH, including obliterative lesions, inflammation, increased cell turnover, and ongoing apoptosis, represent a final common pathway of a disease that can evolve as a consequence of a variety of insults to the lung vasculature.

scholarly journals RhoA increases ASIC1a plasma membrane localization and calcium influx in pulmonary arterial smooth muscle cells following chronic hypoxia

2018 ◽  
Vol 314 (2) ◽  
pp. C166-C176 ◽  
Author(s):  
Lindsay M. Herbert ◽  
Thomas C. Resta ◽  
Nikki L. Jernigan
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Plasma Membrane ◽  
Ion Channel ◽  
Chronic Hypoxia ◽  
Membrane Localization ◽  
Hypoxic Pulmonary Hypertension ◽  
Plasma Membrane Localization ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle

Increases in pulmonary arterial smooth muscle cell (PASMC) intracellular Ca2+ levels and enhanced RhoA/Rho kinase-dependent Ca2+ sensitization are key determinants of PASMC contraction, migration, and proliferation accompanying the development of hypoxic pulmonary hypertension. We previously showed that acid-sensing ion channel 1a (ASIC1a)-mediated Ca2+ entry in PASMC is an important constituent of the active vasoconstriction, vascular remodeling, and right ventricular hypertrophy associated with hypoxic pulmonary hypertension. However, the enhanced ASIC1a-mediated store-operated Ca2+ entry in PASMC from pulmonary hypertensive animals is not dependent on an increase in ASIC1a protein expression, suggesting that chronic hypoxia (CH) stimulates ASIC1a function through other regulatory mechanism(s). RhoA is involved in ion channel trafficking, and levels of activated RhoA are increased following CH. Therefore, we hypothesize that activation of RhoA following CH increases ASIC1a-mediated Ca2+ entry by promoting ASIC1a plasma membrane localization. Consistent with our hypothesis, we found greater plasma membrane localization of ASIC1a following CH. Inhibition of RhoA decreased ASIC1a plasma membrane expression and largely diminished ASIC1a-mediated Ca2+ influx, whereas activation of RhoA had the opposite effect. A proximity ligation assay revealed that ASIC1a and RhoA colocalize in PASMC and that the activation state of RhoA modulates this interaction. Together, our findings show a novel interaction between RhoA and ASIC1a, such that activation of RhoA in PASMC, both pharmacologically and via CH, promotes ASIC1a plasma membrane localization and Ca2+ entry. In addition to enhanced RhoA-mediated Ca2+ sensitization following CH, RhoA can also activate a Ca2+ signal by facilitating ASIC1a plasma membrane localization and Ca2+ influx in pulmonary hypertension.

Expression and activity of cAMP phosphodiesterase isoforms in pulmonary artery smooth muscle cells from patients with pulmonary hypertension: role for PDE1

2007 ◽  
Vol 292 (1) ◽  
pp. L294-L303 ◽  
Author(s):  
Fiona Murray ◽  
Hemal H. Patel ◽  
Ryan Y. S. Suda ◽  
Shen Zhang ◽  
Patricia A. Thistlethwaite ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Cyclic Nucleotide ◽  
Cellular Proliferation ◽  
Muscle Cells ◽  
Pulmonary Vasculature ◽  
Pulmonary Arterial ◽  
Camp Levels ◽  
Expression And Activity

Pulmonary hypertension (PHT) is associated with increased vascular resistance due to sustained contraction and enhanced proliferation of pulmonary arterial smooth muscle cells (PASMC); the abnormal tone and remodeling in the pulmonary vasculature may relate, at least in part, to decreased cyclic nucleotide levels. Cyclic nucleotide phosphodiesterases (PDEs), of which 11 families have been identified, catalyze the hydrolysis of cAMP and cGMP. We tested the hypothesis that PASMC isolated from patients with PHT, either idiopathic pulmonary arterial hypertension (IPAH) or secondary pulmonary hypertension (SPH), have increased expression and activity of PDE isoforms that reduce the responsiveness of agents that raise cellular cAMP. Real-time PCR and immunoblotting demonstrated that the expression of PDE1A, PDE1C, PDE3B, and PDE5A was enhanced in PASMC from both IPAH and SPH patients compared with control PASMC. Consistent with this enhanced expression of PDEs, agonist-stimulated cAMP levels were significantly reduced in IPAH and SPH PASMC unless a PDE inhibitor was present. The use of specific PDE inhibitors revealed that an increase in PDE1 and PDE3 activity largely accounted for reduced agonist-induced cAMP levels and increased proliferation in IPAH and SPH PASMC. Treatment with PDE1C-targeted small interference RNA enhanced cAMP accumulation and inhibited cellular proliferation to a greater extent in PHT PASMC than controls. The results imply that an increase in PDE isoforms, in particular PDE1C, contributes to decreased cAMP and increased proliferation of PASMC in patients with PHT. PDE1 isoforms may provide novel targets for the treatment of both primary and secondary forms of the disease.

scholarly journals Chronic hypoxia upregulates pulmonary arterial ASIC1: a novel mechanism of enhanced store-operated Ca2+ entry and receptor-dependent vasoconstriction

2012 ◽  
Vol 302 (6) ◽  
pp. C931-C940 ◽  
Author(s):  
Nikki L. Jernigan ◽  
Lindsay M. Herbert ◽  
Benjimen R. Walker ◽  
Thomas C. Resta
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Ion Channel ◽  
Vessel Wall ◽  
Wistar Rats ◽  
Chronic Hypoxia ◽  
Pulmonary Arteries ◽  
Intracellular Ca ◽  
Pulmonary Arterial

Acid-sensing ion channel 1 (ASIC1) is a newly characterized contributor to store-operated Ca2+ entry (SOCE) in pulmonary vascular smooth muscle (VSM). Since SOCE is implicated in elevated basal VSM intracellular Ca2+ concentration ([Ca2+]i) and augmented vasoconstriction in chronic hypoxia (CH)-induced pulmonary hypertension, we hypothesized that ASIC1 contributes to these responses. To test this hypothesis, we examined effects of the specific pharmacologic ASIC1a inhibitor, psalmotoxin 1 (PcTX1), on vasoconstrictor and vessel wall [Ca2+]i responses to UTP and KCl (depolarizing stimulus) in fura-2-loaded, pressurized small pulmonary arteries from control and CH (4 wk at 0.5 atm) Wistar rats. PcTX1 had no effect on basal vessel wall [Ca2+]i, but attenuated vasoconstriction and increases in vessel wall [Ca2+]i to UTP in arteries from control and CH rats; normalizing responses between groups. In contrast, responses to the depolarizing stimulus, KCl, were unaffected by CH exposure or PcTX1. Upon examining potential Ca2+ influx mechanisms, we found that PcTX1 prevented augmented SOCE following CH. Exposure to CH resulted in a significant increase in pulmonary arterial ASIC1 protein. This study supports a novel role of ASIC1 in elevated receptor-stimulated vasoconstriction following CH which is likely mediated through increased ASIC1 expression and SOCE.

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