scholarly journals Endothelin-1 contributes to increased NFATc3 activation by chronic hypoxia in pulmonary arteries

2011 ◽  
Vol 301 (2) ◽  
pp. C441-C450 ◽  
Author(s):  
Sergio de Frutos ◽  
Juan Manuel Ramiro Diaz ◽  
Carlos H. Nitta ◽  
Mingma L. Sherpa ◽  
Laura V. Gonzalez Bosc
Keyword(s):  
Nuclear Import ◽  
Actin Polymerization ◽  
Chronic Hypoxia ◽  
Ex Vivo ◽  
Pulmonary Arteries ◽  
Green Fluorescence Protein ◽  
Luciferase Reporter ◽  
Activated T Cells ◽  
Endothelin 1 ◽  
Pulmonary Arterial

Chronic hypoxia (CH) activates the Ca2+-dependent transcription factor nuclear factor of activated T cells isoform c3 (NFATc3) in mouse pulmonary arteries. However, the mechanism of this response has not been explored. Since we have demonstrated that NFATc3 is required for CH-induced pulmonary arterial remodeling, establishing how CH activates NFATc3 is physiologically significant. The goal of this study was to test the hypothesis that endothelin-1 (ET-1) contributes to CH-induced NFATc3 activation. We propose that this mechanism requires increased pulmonary arterial smooth muscle cell (PASMC) intracellular Ca2+ concentration ([Ca2+]i) and stimulation of RhoA/Rho kinase (ROK), leading to calcineurin activation and actin cytoskeleton polymerization, respectively. We found that: 1) CH increases pulmonary arterial pre-pro-ET-1 mRNA expression and lung RhoA activity; 2) inhibition of ET receptors, calcineurin, L-type Ca2+ channels, and ROK blunts CH-induced NFATc3 activation in isolated intrapulmonary arteries from NFAT-luciferase reporter mice; and 3) both ET-1-induced NFATc3 activation in isolated mouse pulmonary arteries ex vivo and ET-1-induced NFATc3-green fluorescence protein nuclear import in human PASMC depend on ROK and actin polymerization. This study suggests that CH increases ET-1 expression, thereby elevating PASMC [Ca2+]i and RhoA/ROK activity. As previously demonstrated, elevated [Ca2+]i is required to activate calcineurin, which dephosphorylates NFATc3, allowing its nuclear import. Here, we demonstrate that ROK increases actin polymerization, thus providing structural support for NFATc3 nuclear transport.

scholarly journals Membrane depolarization is required for pressure-dependent pulmonary arterial tone but not enhanced vasoconstriction to endothelin-1 following chronic hypoxia

2020 ◽  
Vol 10 (4) ◽  
pp. 204589402097355
Author(s):  
Charles E Norton ◽  
Nikki L Jernigan ◽  
Benjimen R Walker ◽  
Thomas C Resta
Keyword(s):  
Chronic Hypoxia ◽  
Pulmonary Arteries ◽  
Rho Kinase ◽  
Membrane Depolarization ◽  
Src Kinases ◽  
Endothelin 1 ◽  
Receptor Inhibition ◽  
Pulmonary Arterial ◽  
Arterial Tone

Enhanced vasoconstriction is increasingly identified as an important contributor to the development of pulmonary hypertension. Chronic hypoxia results in enhanced Rho kinase mediated Ca2+ sensitization contributing to pressure-dependent pulmonary arterial tone as well as augmented vasoconstriction to endothelin-1 and depolarizing stimuli. We sought to investigate the interaction between these vasoconstrictor stimuli in isolated, pressurized, pulmonary arteries. We used the K+ ionophore, valinomycin, to clamp membrane potential (Vm) to investigate the role of membrane depolarization in endothelin-1 and pressure-dependent constriction, and endothelin-1 receptor inhibitors to determine whether membrane depolarization or stretch signal through endothelin-1 receptors. Clamping Vm prevented pressure-dependent tone, but not enhanced vasoconstriction to endothelin-1 following chronic hypoxia. Furthermore, endothelin-1 receptor inhibition had no effect on either pressure-dependent tone or vasoconstriction to KCl. As Src kinases contribute to both pressure-dependent tone and enhanced endothelin-1 vasoconstriction following chronic hypoxia, we further investigated their role in depolarization-induced vasoconstriction. Inhibition of Src kinases attenuated enhanced vasoconstriction to KCl. We conclude that membrane depolarization contributes to pressure-dependent tone but not enhanced vasoconstriction to ET-1, and that Src kinases serve as upstream mediators facilitating enhanced Rho kinase-dependent vasoconstriction following chronic hypoxia.

scholarly journals Actin polymerization contributes to enhanced pulmonary vasoconstrictor reactivity after chronic hypoxia

2018 ◽  
Vol 314 (5) ◽  
pp. H1011-H1021 ◽  
Author(s):  
Laura Weise-Cross ◽  
Michelle A. Sands ◽  
Joshua R. Sheak ◽  
Brad R. S. Broughton ◽  
Jessica B. Snow ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Actin Polymerization ◽  
Chronic Hypoxia ◽  
Pulmonary Arteries ◽  
Rho Kinase ◽  
Reactive Oxygen ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Pulmonary Arterial ◽  
Arterial Constriction

Chronic hypoxia (CH) augments basal and endothelin-1 (ET-1)-induced pulmonary vasoconstrictor reactivity through reactive oxygen species (ROS) generation and RhoA/Rho kinase (ROCK)-dependent myofilament Ca2+ sensitization. Because ROCK promotes actin polymerization and the actin cytoskeleton regulates smooth muscle tension, we hypothesized that actin polymerization is required for enhanced basal and ET-1-dependent vasoconstriction after CH. To test this hypothesis, both end points were monitored in pressurized, endothelium-disrupted pulmonary arteries (fourth-fifth order) from control and CH (4 wk at 0.5 atm) rats. The actin polymerization inhibitors cytochalasin and latrunculin attenuated both basal and ET-1-induced vasoconstriction only in CH vessels. To test whether CH directly alters the arterial actin profile, we measured filamentous actin (F-actin)-to-globular actin (G-actin) ratios by fluorescent labeling of F-actin and G-actin in fixed pulmonary arteries and actin sedimentation assays using homogenized pulmonary artery lysates. We observed no difference in actin polymerization between groups under baseline conditions, but ET-1 enhanced actin polymerization in pulmonary arteries from CH rats. This response was blunted by the ROS scavenger tiron, the ROCK inhibitor fasudil, and the mDia (RhoA effector) inhibitor small-molecule inhibitor of formin homology domain 2. Immunoblot analysis revealed an effect of CH to increase both phosphorylated (inactive) and total levels of the actin disassembly factor cofilin but not phosphorylated cofilin-to-total cofilin ratios. We conclude that actin polymerization contributes to increased basal pulmonary arterial constriction and ET-1-induced vasoconstrictor reactivity after CH in a ROS- and ROCK-dependent manner. Our results further suggest that enhanced ET-1-mediated actin polymerization after CH is dependent on mDia but independent of changes in the phosphorylated cofilin-to-total cofilin ratio. NEW & NOTEWORTHY This research is the first to demonstrate a role for actin polymerization in chronic hypoxia-induced basal pulmonary arterial constriction and enhanced agonist-induced vasoconstrictor activity. These results suggest that a reactive oxygen species-Rho kinase-actin polymerization signaling pathway mediates this response and may provide a mechanistic basis for the vasoconstrictor component of pulmonary hypertension.

scholarly journals Pentaerythritol Tetranitrate In Vivo Treatment Improves Oxidative Stress and Vascular Dysfunction by Suppression of Endothelin-1 Signaling in Monocrotaline-Induced Pulmonary Hypertension

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Sebastian Steven ◽  
Matthias Oelze ◽  
Moritz Brandt ◽  
Elisabeth Ullmann ◽  
Swenja Kröller-Schön ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pulmonary Hypertension ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Whole Blood ◽  
Pulmonary Arteries ◽  
Vascular Wall ◽  
Pentaerythritol Tetranitrate ◽  
Endothelin 1 ◽  
Pulmonary Arterial

Objective. Oxidative stress and endothelial dysfunction contribute to pulmonary arterial hypertension (PAH). The role of the nitrovasodilator pentaerythritol tetranitrate (PETN) on endothelial function and oxidative stress in PAH has not yet been defined.Methods and Results. PAH was induced by monocrotaline (MCT, i.v.) in Wistar rats. Low (30 mg/kg; MCT30), middle (40 mg/kg; MCT40), or high (60 mg/kg; MCT60) dose of MCT for 14, 28, and 42 d was used. MCT induced endothelial dysfunction, pulmonary vascular wall thickening, and fibrosis, as well as protein tyrosine nitration. Pulmonary arterial pressure and heart/body and lung/body weight ratio were increased in MCT40 rats (28 d) and reduced by oral PETN (10 mg/kg, 24 d) therapy. Oxidative stress in the vascular wall, in the heart, and in whole blood as well as vascular endothelin-1 signaling was increased in MCT40-treated rats and normalized by PETN therapy, likely by upregulation of heme oxygenase-1 (HO-1). PETN therapy improved endothelium-dependent relaxation in pulmonary arteries and inhibited endothelin-1-induced oxidative burst in whole blood and the expression of adhesion molecule (ICAM-1) in endothelial cells.Conclusion. MCT-induced PAH impairs endothelial function (aorta and pulmonary arteries) and increases oxidative stress whereas PETN markedly attenuates these adverse effects. Thus, PETN therapy improves pulmonary hypertension beyond its known cardiac preload reducing ability.

Endothelin-1-induced pulmonary arterial dilation is reduced by N omega-nitro-L-arginine in fetal lambs

1992 ◽  
Vol 72 (5) ◽  
pp. 1730-1734 ◽  
Author(s):  
M. L. Tod ◽  
S. Cassin
Keyword(s):  
Pulmonary Veins ◽  
Pulmonary Arteries ◽  
Vascular Occlusion ◽  
Pressure Gradients ◽  
Endothelin 1 ◽  
Pulmonary Vasodilator ◽  
Pulmonary Capillary ◽  
Occlusion Technique ◽  
Pulmonary Arterial ◽  
Arterial Dilation

Endothelin-1 (ET-1) is a pulmonary vasodilator in the unventilated fetal lamb. The site and mechanism of this vasodilator response were investigated in isolated blood-perfused lungs from nine fetal lambs delivered at 127–140 days gestation. The vascular occlusion technique was used to partition the total pulmonary pressure gradient into pressure gradients across large and small arteries (delta PLA and delta PSA, respectively) and veins (delta PV). Injection of ET-1 (74 ng/kg) into the pulmonary artery significantly decreased delta PLA from 12.4 +/- 2.1 to 5.2 +/- 1.1 mmHg and delta PSA from 49.2 +/- 2.7 to 31.3 +/- 4.9 mmHg. The pressure measured by double occlusion, an estimate of pulmonary capillary pressure, was not altered by ET-1 (15.5 +/- 1.0 vs. 14.8 +/- 1.0 mmHg), indicating that ET-1 had no effect on pulmonary veins. Addition of N omega-nitro-L-arginine (estimated perfusate concentration 2–6 mM), an analogue of L-arginine that inhibits the production of endothelium-derived relaxing factor (EDRF), significantly attenuated the dilator responses to acetylcholine (10 micrograms) and ET-1 (74 ng/kg) by 35 and 56%, respectively. These results in unventilated fetal lungs indicate that 1) ET-1 dilates both large and small pulmonary arteries with no effect on pulmonary veins, and 2) this effect is mediated in part through the action of the EDRF pathway.

Sex Differences in Right Ventricular-Vascular Coupling and Pulmonary Artery Impedance in Response to Chronic Hypoxia and Recovery

2012 ◽  
Author(s):  
Aiping Liu ◽  
Lian Tian ◽  
Diana M. Tabima ◽  
Naomi C. Chesler
Keyword(s):  
Pulmonary Artery ◽  
Chronic Hypoxia ◽  
Pulmonary Arteries ◽  
Pulmonary Artery Hypertension ◽  
Vascular Impedance ◽  
Female Predominance ◽  
Collagen Accumulation ◽  
Dominant Disease ◽  
Pulmonary Arterial

Pulmonary artery hypertension (PAH) is a female dominant disease (the female-to-male ratio is 4:1), characterized by small distal pulmonary arterial narrowing and large proximal arterial stiffening, which increase right ventricle (RV) afterload and ultimately lead to RV failure [1,2]. Our recent studies have shown that collagen accumulation induced by chronic hypoxia increases the stiffness of the large extralobar pulmonary arteries (PAs) [3], and affects pulmonary vascular impedance (PVZ) [4]. The role of collagen in the female predominance in developing PAH has not been explored to date.

Thromboxane inhibition reduces an early stage of chronic hypoxia-induced pulmonary hypertension in piglets

2005 ◽  
Vol 99 (2) ◽  
pp. 670-676 ◽  
Author(s):  
Candice D. Fike ◽  
Yongmei Zhang ◽  
Mark R. Kaplowitz
Keyword(s):  
Pulmonary Hypertension ◽  
Chronic Hypoxia ◽  
Early Stage ◽  
Pulmonary Arteries ◽  
Pulmonary Wedge Pressure ◽  
Thromboxane Synthase Inhibitor ◽  
Pulmonary Arterial ◽  
Synthase Inhibitor ◽  
Air Control ◽  
Arterial Responses

The pulmonary vasoconstrictor, thromboxane, may contribute to the development of pulmonary hypertension. Our objective was to determine whether a combined thromboxane synthase inhibitor-receptor antagonist, terbogrel, prevents pulmonary hypertension and the development of aberrant pulmonary arterial responses in newborn piglets exposed to 3 days of hypoxia. Piglets were maintained in room air (control) or 11% O2 (hypoxic) for 3 days. Some hypoxic piglets received terbogrel (10 mg/kg po bid). Pulmonary arterial pressure, pulmonary wedge pressure, and cardiac output were measured in anesthetized animals. A cannulated artery technique was used to measure responses to acetylcholine. Pulmonary vascular resistance for terbogrel-treated hypoxic piglets was almost one-half the value of untreated hypoxic piglets but remained greater than values for control piglets. Dilation to acetylcholine in preconstricted pulmonary arteries was greater for terbogrel-treated hypoxic than for untreated hypoxic piglets, but it was less for pulmonary arteries from both groups of hypoxic piglets than for control piglets. Terbogrel may ameliorate pulmonary artery dysfunction and attenuate the development of chronic hypoxia-induced pulmonary hypertension in newborns.

Polycythemia and vascular remodeling in chronic hypoxic pulmonary hypertension in guinea pigs

1991 ◽  
Vol 71 (6) ◽  
pp. 2218-2223 ◽  
Author(s):  
S. P. Janssens ◽  
B. T. Thompson ◽  
C. R. Spence ◽  
C. A. Hales
Keyword(s):  
Pulmonary Hypertension ◽  
Guinea Pigs ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Pulmonary Arterial Pressure ◽  
Pulmonary Arteries ◽  
Similar Degree ◽  
Similar Tendency ◽  
Pulmonary Arterial ◽  
Medial Thickening

Chronic hypoxia increases pulmonary arterial pressure (PAP) as a result of vasoconstriction, polycythemia, and vascular remodeling with medial thickening. To determine whether preventing the polycythemia with repeated bleeding would diminish the pulmonary hypertension and remodeling, we compared hemodynamic and histological profiles in hypoxic bled (HB, n = 6) and hypoxic polycythemic guinea pigs (H, n = 6). After 10 days in hypoxia (10% O2), PAP was increased from 10 +/- 1 (SE) mmHg in room air controls (RA, n = 5) to 20 +/- 1 mmHg in H (P less than 0.05) but was lower in HB (15 +/- 1 mmHg, P less than 0.05 vs. H). Cardiac output and pulmonary artery vasoreactivity did not differ among groups. Total pulmonary vascular resistance increased from 0.072 +/- 0.011 mmHg.ml-1.min in RA to 0.131 mmHg.ml-1.min in H but was significantly lower in HB (0.109 +/- 0.006 mmHg.ml-1.min). Hematocrit increased with hypoxia (57 +/- 3% in H vs. 42 +/- 1% in RA, P less than 0.05), and bleeding prevented the increase (46 +/- 4% in HB, P less than 0.05 vs. H only). The proportion of thick-walled peripheral pulmonary vessels (53.2 +/- 2.9% in HB and 50.6 +/- 4.8% in H vs. 31.6 +/- 2.6% in RA, P less than 0.05) and the percent medial thickness of pulmonary arteries adjacent to alveolar ducts (7.2 +/- 0.6% in HB and 7.0 +/- 0.4% in H vs. 5.2 +/- 0.4% in RA, P less than 0.05) increased to a similar degree in both hypoxic groups. A similar tendency was present in larger bronchiolar vessels.(ABSTRACT TRUNCATED AT 250 WORDS)

Progressive loss of vasodilator responsive component of pulmonary hypertension in neonatal calves exposed to 4,570 m

1993 ◽  
Vol 265 (6) ◽  
pp. H2175-H2183 ◽  
Author(s):  
A. G. Durmowicz ◽  
E. C. Orton ◽  
K. R. Stenmark
Keyword(s):  
Pulmonary Hypertension ◽  
Chronic Exposure ◽  
Chronic Hypoxia ◽  
Pulmonary Arteries ◽  
Barometric Pressure ◽  
Hypoxic Conditions ◽  
Progressive Loss ◽  
Vessel Structure ◽  
Pulmonary Arterial ◽  
Neonatal Calves

Severe neonatal pulmonary hypertension (PH) may have both reversible (vasoconstrictive) and “fixed” (vasodilator unresponsive) components. To assess when and to what degree vasodilator unresponsive PH developed in the neonate, pulmonary arterial pressures (PAP) and cardiac outputs (CO) were measured, and total pulmonary resistances (TPR) were calculated in neonatal calves exposed to chronic hypoxia (CH) (barometric pressure of 430 mmHg = 4,570 m) for 1, 3, 7, and 14 days under both normoxic (barometric pressure of 640 mmHg = 1,500 m) and hypoxic conditions with and without an infusion of the vasodilator acetylcholine (ACh). Studies were done at 4 h and at 2, 4, 8, and 15 days of life in both control and CH animals. The fixed component of PH was defined as that PAP or TPR above the control baseline value which remained in CH animals after an infusion ACh at 1,500 m. Small pulmonary arteries were also examined histologically in an attempt to correlate relative changes in the reversible and fixed elements of PH with alterations in vessel structure. Chronic exposure to 4,570 m altitude prevented the normal postnatal fall in PAP and TPR observed in control animals. Instead, PAP, TPR, and the structure of small pulmonary arteries initially remained similar to those of the 4-h-old newborn. By 7 days exposure to 4,570 m, a significant element of fixed PH developed, which increased dramatically between the 7- and 14-day exposure periods and appeared to correlate with a narrowed pulmonary artery lumen and increased medial and adventitial thickness.(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelin-1 decreases endothelial NOS expression and activity through ETA receptor-mediated generation of hydrogen peroxide

2005 ◽  
Vol 288 (3) ◽  
pp. L480-L487 ◽  
Author(s):  
Stephen Wedgwood ◽  
Stephen M. Black
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Promoter Activity ◽  
Pulmonary Arteries ◽  
Feedback Mechanism ◽  
Enos Gene ◽  
Endothelin 1 ◽  
Protein Levels ◽  
Pulmonary Arterial ◽  
Endothelin B

Similar to infants born with persistent pulmonary hypertension of the newborn (PPHN), there is an increase in circulating endothelin-1 (ET-1) and decreased endothelial nitric oxide synthase (eNOS) gene expression in an ovine model of PPHN. These abnormalities lead to vasoconstriction and vascular remodeling. Our previous studies have demonstrated that reactive oxygen species (ROS) levels are elevated in the pulmonary arteries from PPHN lambs and that ET-1 increases ROS production in pulmonary arterial smooth muscle cells (PASMC) in culture. Thus the objective of this study was to determine whether there was a feedback mechanism between the ET-1-mediated increase in ROS in fetal PASMC (FPASMC) and a decrease in eNOS gene expression in fetal pulmonary arterial endothelial cells (FPAEC). Our results indicate that ET-1 increased H2O2 levels in FPASMC in an endothelin A receptor-dependent fashion. This was observed in both FPASMC monoculture and in cocultures of FPASMC and FPAEC. Conversely, ET-1 decreased H2O2 levels in FPAEC monoculture in an endothelin B receptor-dependent fashion. Furthermore, ET-1 decreased eNOS promoter activity by 40% in FPAEC in coculture with FPASMC. Promoter activity was restored in the presence of catalase. In FPAEC in monoculture treated with 0–100 μM H2O2, 12 μM had no effect on eNOS promoter activity, but it increased eNOS protein levels by 50%. However, at 100 μM, H2O2 decreased eNOS promoter activity and protein levels in FPAEC by 79 and 40%, respectively. These data suggest a role for smooth muscle cell-derived H2O2 in ET-1-mediated downregulation of eNOS expression in children born with PPHN.

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