Cyclic stretch increases VEGF expression in pulmonary arterial smooth muscle cells via TGF-β1 and reactive oxygen species: a requirement for NAD(P)H oxidase

2005 ◽  
Vol 289 (2) ◽  
pp. L288-L289 ◽  
Author(s):  
Eugenia Mata-Greenwood ◽  
Albert Grobe ◽  
Sanjiv Kumar ◽  
Yelina Noskina ◽  
Stephen M. Black
Keyword(s):  
Reactive Oxygen Species ◽  
Blood Flow ◽  
Smooth Muscle ◽  
Reactive Oxygen ◽  
Cyclic Stretch ◽  
Oxygen Species ◽  
Vegf Expression ◽  
Pulmonary Vessels ◽  
Pulmonary Arterial ◽  
Tgf Β1

Our previous studies have indicated that transforming growth factor (TGF)-β1 and VEGF expression are increased in the smooth muscle cell (SMC) layer of the pulmonary vessels of lambs with pulmonary hypertension secondary to increased pulmonary blood flow. Furthermore, we found that TGF-β1 expression increased before VEGF. Because of the increased blood flow in the shunt lambs, the SMC in the pulmonary vessels are exposed to increased levels of the mechanical force, cyclic stretch. Thus, in this study, using primary cultures of pulmonary arterial SMC isolated from pulmonary arteries of 4-wk-old lambs, we investigated the role of cyclic stretch in the apparent coordinated regulation of TGF-β1 and VEGF. Our results demonstrated that cyclic stretch induced a significant increase in VEGF expression both at the mRNA and protein levels ( P < 0.05). The increased VEGF mRNA was preceded by both an increased expression and secretion of TGF-β1 and an increase in reactive oxygen species (ROS) generation. In addition, a neutralizing antibody against TGF-β1 abolished the cyclic stretch-dependent increases in both superoxide generation and VEGF expression. Our data also demonstrated that cyclic stretch activated an NAD(P)H oxidase that was TGF-β1 dependent and that NAD(P)H oxidase inhibitors abolished the cyclic stretch-dependent increase in VEGF expression. Therefore, our results indicate that cyclic stretch upregulates VEGF expression via the TGF-β1-dependent activation of NAD(P)H oxidase and increased generation of ROS.

Reactive oxygen species alter contractile properties of pulmonary arterial smooth muscle

1990 ◽  
Vol 68 (12) ◽  
pp. 1581-1589 ◽  
Author(s):  
R. A. Rhoades ◽  
C. S. Packer ◽  
D. A. Roepke ◽  
N. Jin ◽  
R. A. Meiss
Keyword(s):  
Reactive Oxygen Species ◽  
Smooth Muscle ◽  
Oxygen Radicals ◽  
Contractile Response ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Arterial Smooth Muscle ◽  
Pulmonary Arterial ◽  
Recovery Response ◽  
Pulmonary Arterial Smooth Muscle

Reactive oxygen species alter pulmonary arterial vascular tone and cause changes in pulmonary vascular resistance. The objective of this investigation was to determine direct effects of oxygen radicals on the contractile properties of pulmonary arterial smooth muscle. Isolated pulmonary arterial rings from Sprague–Dawley rats were placed in tissue baths containing Earle's balanced salt solution (gassed with 95% O2 – 5% CO2, 37 °C, pH 7.4). Vessels were contracted with 80 mM KCl to establish maximum active force production (PO). All other responses were normalized as percentages of PO for comparative purposes. Reactive oxygen metabolites were generated enzymatically with either the xanthine oxidase (XO) reaction or me glucose oxidase (GO) reaction, or hydrogen peroxide (H2O2) was added directly to the muscle bath. Exposure to XO, GO, or to H2O2 resulted in a contractile response that was sustained during the 30-min exposure period. The muscle fully relaxed following removal of the reactive oxygen species. Resting tension remained unchanged throughout the experimental period, suggesting no functional change in membrane potential. The contractile response was dose dependent and was not prevented by either cyclooxygenase or lipoxygenase inhibition, or by removal of the endothelium. Pretreatment of vessels with superoxide dismutase (SOD) partially blocked the XO-induced contraction, while mannitol or deferoxamine had no effect on the response to XO. However, pretreatment with catalase (CAT) completely blocked the XO-induced contraction. These data suggest that superoxide ions and hydrogen peroxide are the major causative agents. Following O2-radical exposure, vessels showed a decrease in contractile responsiveness to 80 mM KCl (recovery response), suggesting damage to the smooth muscle cells. Administration of SOD or CAT alone significantly improved the recovery response to 80 mM KCl, while SOD plus CAT offered complete protection resulting in final responses to high K+ that were 100% of PO. Vessels precontracted with a submaximal dose of KCl or 5-hydroxytryptamine and then exposed to O2 radicals produced contractile responses that were more than additive, suggesting that "priming" the vessel potentiated reactive oxygen-mediated contraction. These data show that reactive oxygen species can act directly as vasoconstrictors, while simultaneously damaging the arterial smooth muscle such that subsequent contractility is impaired.Key words: oxygen radicals, pulmonary circulation, pulmonary artery, vascular smooth muscle.

scholarly journals Mechanisms of NFATc3 activation by increased superoxide and reduced hydrogen peroxide in pulmonary arterial smooth muscle

2014 ◽  
Vol 307 (10) ◽  
pp. C928-C938 ◽  
Author(s):  
Juan Manuel Ramiro-Diaz ◽  
Wieslawa Giermakowska ◽  
John M. Weaver ◽  
Nikki L. Jernigan ◽  
Laura V. Gonzalez Bosc
Keyword(s):  
Reactive Oxygen Species ◽  
Smooth Muscle ◽  
Actin Polymerization ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Arterial Smooth Muscle ◽  
Activated T Cells ◽  
Intracellular Ca ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle

We recently demonstrated increased superoxide (O2·−) and decreased H2O2 levels in pulmonary arteries of chronic hypoxia-exposed wild-type and normoxic superoxide dismutase 1 (SOD1) knockout mice. We also showed that this reciprocal change in O2·− and H2O2 is associated with elevated activity of nuclear factor of activated T cells isoform c3 (NFATc3) in pulmonary arterial smooth muscle cells (PASMC). This suggests that an imbalance in reactive oxygen species levels is required for NFATc3 activation. However, how such imbalance activates NFATc3 is unknown. This study evaluated the importance of O2·− and H2O2 in the regulation of NFATc3 activity. We tested the hypothesis that an increase in O2·− enhances actin cytoskeleton dynamics and a decrease in H2O2 enhances intracellular Ca2+ concentration, contributing to NFATc3 nuclear import and activation in PASMC. We demonstrate that, in PASMC, endothelin-1 increases O2·− while decreasing H2O2 production through the decrease in SOD1 activity without affecting SOD protein levels. We further demonstrate that O2·− promotes, while H2O2 inhibits, NFATc3 activation in PASMC. Additionally, increased O2·−-to-H2O2 ratio activates NFATc3, even in the absence of a Gq protein-coupled receptor agonist. Furthermore, O2·−-dependent actin polymerization and low intracellular H2O2 concentration-dependent increases in intracellular Ca2+ concentration contribute to NFATc3 activation. Together, these studies define important and novel regulatory mechanisms of NFATc3 activation in PASMC by reactive oxygen species.

scholarly journals Reactive oxygen species induced Ca2+ influx via TRPV4 and microvascular endothelial dysfunction in the SU5416/hypoxia model of pulmonary arterial hypertension

2018 ◽  
Vol 314 (5) ◽  
pp. L893-L907 ◽  
Author(s):  
Karthik Suresh ◽  
Laura Servinsky ◽  
Haiyang Jiang ◽  
Zahna Bigham ◽  
Xin Yun ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Endothelial Cells ◽  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Reactive Oxygen ◽  
Transient Receptor Potential Vanilloid ◽  
Oxygen Species ◽  
Pulmonary Arterial ◽  
Microvascular Endothelial

Pulmonary arterial hypertension (PAH) is a lethal disease characterized by elevations in pulmonary arterial pressure, in part due to formation of occlusive lesions in the distal arterioles of the lung. These complex lesions may comprise multiple cell types, including endothelial cells (ECs). To better understand the molecular mechanisms underlying EC dysfunction in PAH, lung microvascular endothelial cells (MVECs) were isolated from normoxic rats (N-MVECs) and rats subjected to SU5416 plus hypoxia (SuHx), an experimental model of PAH. Compared with N-MVECs, MVECs isolated from SuHx rats (SuHx-MVECs) appeared larger and more spindle shaped morphologically and expressed canonical smooth muscle cell markers smooth muscle-specific α-actin and myosin heavy chain in addition to endothelial markers such as Griffonia simplicifolia and von Willebrand factor. SuHx-MVEC mitochondria were dysfunctional, as evidenced by increased fragmentation/fission, decreased oxidative phosphorylation, and increased reactive oxygen species (ROS) production. Functionally, SuHx-MVECs exhibited increased basal levels of intracellular calcium concentration ([Ca2+]i) and enhanced migratory and proliferative capacity. Treatment with global (TEMPOL) or mitochondria-specific (MitoQ) antioxidants decreased ROS levels and basal [Ca2]i in SuHx-MVECs. TEMPOL and MitoQ also decreased migration and proliferation in SuHx-MVECs. Additionally, inhibition of ROS-induced Ca2+ entry via pharmacologic blockade of transient receptor potential vanilloid-4 (TRPV4) attenuated [Ca2]i, migration, and proliferation. These findings suggest a role for mitochondrial ROS-induced Ca2+ influx via TRPV4 in promoting abnormal migration and proliferation in MVECs in this PAH model.

scholarly journals Sodium Glucose Co-Transporter 2 Inhibitors Ameliorate Endothelium Barrier Dysfunction Induced by Cyclic Stretch through Inhibition of Reactive Oxygen Species

2021 ◽  
Vol 22 (11) ◽  
pp. 6044
Author(s):  
Xiaoling Li ◽  
Gregor Römer ◽  
Raphaela P. Kerindongo ◽  
Jeroen Hermanides ◽  
Martin Albrecht ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Endothelial Cells ◽  
Reactive Oxygen ◽  
Cyclic Stretch ◽  
Cell Permeability ◽  
Ros Production ◽  
Oxygen Species ◽  
Barrier Dysfunction ◽  
Human Coronary Artery ◽  
Oxidative Effect

SGLT-2i’s exert direct anti-inflammatory and anti-oxidative effects on resting endothelial cells. However, endothelial cells are constantly exposed to mechanical forces such as cyclic stretch. Enhanced stretch increases the production of reactive oxygen species (ROS) and thereby impairs endothelial barrier function. We hypothesized that the SGLT-2i’s empagliflozin (EMPA), dapagliflozin (DAPA) and canagliflozin (CANA) exert an anti-oxidative effect and alleviate cyclic stretch-induced endothelial permeability in human coronary artery endothelial cells (HCAECs). HCAECs were pre-incubated with one of the SGLT-2i’s (1 µM EMPA, 1 µM DAPA and 3 µM CANA) for 2 h, followed by 10% stretch for 24 h. HCAECs exposed to 5% stretch were considered as control. Involvement of ROS was measured using N-acetyl-l-cysteine (NAC). The sodium-hydrogen exchanger 1 (NHE1) and NADPH oxidases (NOXs) were inhibited by cariporide, or GKT136901, respectively. Cell permeability and ROS were investigated by fluorescence intensity imaging. Cell permeability and ROS production were increased by 10% stretch; EMPA, DAPA and CANA decreased this effect significantly. Cariporide and GKT136901 inhibited stretch-induced ROS production but neither of them further reduced ROS production when combined with EMPA. SGLT-2i’s improve the barrier dysfunction of HCAECs under enhanced stretch and this effect might be mediated through scavenging of ROS. Anti-oxidative effect of SGLT-2i’s might be partially mediated by inhibition of NHE1 and NOXs.

scholarly journals Calcific Uremic Arteriolopathy: Pathophysiology, Reactive Oxygen Species and Therapeutic Approaches

2010 ◽  
Vol 3 (2) ◽  
pp. 109-121 ◽  
Author(s):  
Kurt M. Sowers ◽  
Melvin R. Hayden
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Chronic Kidney Disease ◽  
Smooth Muscle ◽  
Kidney Disease ◽  
Vascular Smooth Muscle ◽  
Reactive Oxygen ◽  
Morbidity And Mortality ◽  
Oxygen Species ◽  
Calcific Uremic Arteriolopathy

Calcific uremic arteriolopathy (CUA)/calciphylaxis is an important cause of morbidity and mortality in patients with chronic kidney disease requiring renal replacement. Once thought to be rare, it is being increasingly recognized and reported on a global scale. The uremic milieu predisposes to multiple metabolic toxicities including increased levels of reactive oxygen species and inflammation. Increased oxidative stress and inflammation promote this arteriolopathy by adversely affecting endothelial function resulting in a prothrombotic milieu and significant remodeling effects on vascular smooth muscle cells. These arteriolar pathological effects include intimal hyperplasia, inflammation, endovascular fibrosis and vascular smooth muscle cell apoptosis and differentiation into bone forming osteoblast-like cells resulting in medial calcification. Systemic factors promoting this vascular condition include elevated calcium, parathyroid hormone and hyperphosphatemia with consequent increases in the calcium × phosphate product. The uremic milieu contributes to a marked increased in upstream reactive oxygen species—oxidative stress and subsequent downstream increased inflammation, in part, via activation of the nuclear transcription factor NFκB and associated downstream cytokine pathways. Consitutive anti-calcification proteins such as Fetuin-A and matrix GLA proteins and their signaling pathways may be decreased, which further contributes to medial vascular calcification. The resulting clinical entity is painful, debilitating and contributes to the excess morbidity and mortality associated with chronic kidney disease and end stage renal disease. These same histopathologic conditions also occur in patients without uremia and therefore, the term calcific obliterative arteriolopathy could be utilized in these conditions.

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