scholarly journals Endothelial pannexin 1–TRPV4 channel signaling lowers pulmonary arterial pressure in mice

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Zdravka Daneva ◽  
Matteo Ottolini ◽  
Yen Lin Chen ◽  
Eliska Klimentova ◽  
Maniselvan Kuppusamy ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Transient Receptor Potential ◽  
Pulmonary Arterial Pressure ◽  
Pulmonary Vasculature ◽  
Transient Receptor Potential Vanilloid ◽  
Caveolin 1 ◽  
Pannexin 1 ◽  
Pulmonary Arterial ◽  
Atp Efflux ◽  
Trpv4 Channel

Pannexin 1 (Panx1), an ATP-efflux pathway, has been linked with inflammation in pulmonary capillaries. However, the physiological roles of endothelial Panx1 in the pulmonary vasculature are unknown. Endothelial transient receptor potential vanilloid 4 (TRPV4) channels lower pulmonary artery (PA) contractility and exogenous ATP activates endothelial TRPV4 channels. We hypothesized that endothelial Panx1–ATP–TRPV4 channel signaling promotes vasodilation and lowers pulmonary arterial pressure (PAP). Endothelial, but not smooth muscle, knockout of Panx1 increased PA contractility and raised PAP in mice. Flow/shear stress increased ATP efflux through endothelial Panx1 in PAs. Panx1-effluxed extracellular ATP signaled through purinergic P2Y2 receptor (P2Y2R) to activate protein kinase Cα (PKCα), which in turn activated endothelial TRPV4 channels. Finally, caveolin-1 provided a signaling scaffold for endothelial Panx1, P2Y2R, PKCα, and TRPV4 channels in PAs, promoting their spatial proximity and enabling signaling interactions. These results indicate that endothelial Panx1–P2Y2R–TRPV4 channel signaling, facilitated by caveolin-1, reduces PA contractility and lowers PAP in mice.

scholarly journals Endothelial Pannexin 1–TRPV4 channel signaling lowers pulmonary arterial pressure

2021 ◽  
Author(s):  
Zdravka Daneva ◽  
Matteo Ottolini ◽  
Yen-Lin Chen ◽  
Eliska Klimentova ◽  
Soham A. Shah ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Transient Receptor Potential ◽  
Pulmonary Arterial Pressure ◽  
Extracellular Atp ◽  
Spatial Proximity ◽  
Transient Receptor Potential Vanilloid ◽  
Caveolin 1 ◽  
Pannexin 1 ◽  
Pulmonary Arterial ◽  
Trpv4 Channel

AbstractPannexin 1 (Panx1) is an ATP-efflux channel that controls endothelial function in the systemic circulation. However, the roles of endothelial Panx1 in resistance-sized pulmonary arteries (PAs) are unknown. Extracellular ATP dilates PAs through activation of endothelial TRPV4 (transient receptor potential vanilloid 4) ion channels. We hypothesized that endothelial Panx1–ATP– TRPV4 channel signaling promotes vasodilation and lowers pulmonary arterial pressure (PAP). Endothelial, but not smooth muscle, knockout of Panx1 or TRPV4 increased PA contractility and raised PAP. Panx1-effluxed extracellular ATP signaled through purinergic P2Y2 receptor (P2Y2R) to activate protein kinase Cα (PKCα), which in turn activated endothelial TRPV4 channels. Finally, caveolin-1 provided a signaling scaffold for endothelial Panx1, P2Y2R, PKCα, and TRPV4 channels in PAs, promoting their spatial proximity and enabling signaling interactions. These results indicate that endothelial Panx1–P2Y2R–TRPV4 channel signaling, facilitated by caveolin-1, reduces PA contractility and lowers PAP.

scholarly journals Caveolar peroxynitrite formation impairs endothelial TRPV4 channels and elevates pulmonary arterial pressure in pulmonary hypertension

2021 ◽  
Vol 118 (17) ◽  
pp. e2023130118
Author(s):  
Zdravka Daneva ◽  
Corina Marziano ◽  
Matteo Ottolini ◽  
Yen-Lin Chen ◽  
Thomas M. Baker ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Endothelial Cell ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Pulmonary Arteries ◽  
Lung Edema ◽  
Structural Protein ◽  
Caveolin 1 ◽  
Pulmonary Arterial ◽  
Trpv4 Channel

Recent studies have focused on the contribution of capillary endothelial TRPV4 channels to pulmonary pathologies, including lung edema and lung injury. However, in pulmonary hypertension (PH), small pulmonary arteries are the focus of the pathology, and endothelial TRPV4 channels in this crucial anatomy remain unexplored in PH. Here, we provide evidence that TRPV4 channels in endothelial cell caveolae maintain a low pulmonary arterial pressure under normal conditions. Moreover, the activity of caveolar TRPV4 channels is impaired in pulmonary arteries from mouse models of PH and PH patients. In PH, up-regulation of iNOS and NOX1 enzymes at endothelial cell caveolae results in the formation of the oxidant molecule peroxynitrite. Peroxynitrite, in turn, targets the structural protein caveolin-1 to reduce the activity of TRPV4 channels. These results suggest that endothelial caveolin-1–TRPV4 channel signaling lowers pulmonary arterial pressure, and impairment of endothelial caveolin-1–TRPV4 channel signaling contributes to elevated pulmonary arterial pressure in PH. Thus, inhibiting NOX1 or iNOS activity, or lowering endothelial peroxynitrite levels, may represent strategies for restoring vasodilation and pulmonary arterial pressure in PH.

Abstract 16629: Endothelial Caveolin-1-trpv4 Regulation of Pulmonary Arterial Pressure and Impairment in Pulmonary Hypertension

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Zdravka Daneva ◽  
Corina Marziano ◽  
Matteo Ottolini ◽  
YEN LIN CHEN ◽  
Kwangseok Hong ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Mouse Models ◽  
Pulmonary Arterial Pressure ◽  
Scaffolding Protein ◽  
Channel Activity ◽  
Caveolin 1 ◽  
Pulmonary Arterial ◽  
Trpv4 Channel

Background: Pulmonary hypertension (PH) is a degenerative disorder that is characterized by elevated vascular resistance and pulmonary arterial pressure (PAP). Endothelial transient receptor potential vanilloid 4 (TRPV4 EC ) ion channels represent an important Ca 2+ influx signaling mechanism that promotes vasodilation of small pulmonary arteries (PAs). Scaffolding protein caveolin-1 (Cav-1) has been shown to precipitate with TRPV4 channels in pulmonary endothelial cells in culture. Hypothesis: We hypothesized that the endothelial Cav-1-TRPV4 channel signaling in small PAs lowers PAP, and is impaired in PH. Methods: Inducible endothelium-specific KO mice for TRPV4 channel or Cav-1 were used to study the role of Cav-1-TRPV4 signaling in the regulation of resting PAP. Endothelium-specific P2Y2 receptor KO mice were used to test if Cav-1 provides a signaling scaffold for purinergic activation of TRPV4 EC channels. Endothelial Cav-1-TRPV4 signaling was assessed in PAs from two PH mouse models and PH patients. The role of NADPH oxidase (NOX1)- and inducible nitric oxide synthase (iNOS)-mediated peroxynitrite (PN), an oxidant molecule, in impairing Cav-1-TRPV4 signaling in PH was evaluated using NOX1-/- and iNOS-/- mice and pharmacological inhibitors. Results: We show that endothelial Cav-1-TRPV4 signaling in small PAs lowers resting PAP, and protects against the pathogenesis of PH. Endothelial Cav-1 provides a signaling scaffold for the activation of TRPV4 channels by endogenous purinergic receptor signaling. Moreover, TRPV4 EC channel activity and Cav-1-TRPV4 signaling are impaired in small PAs from two mouse models of PH and PH patients. Elevated levels of NOX1 and iNOS enzymes in caveolae resulted in PN formation close to Cav-1 in PH. Elevated PN targeted Cav-1 to lower Cav-1-TRPV4 signaling, thereby contributing to impaired vasodilation and increased PAP. Pharmacological inhibition of NOX1, iNOS, or PN rescued TRPV4 EC channel activity and vasodilation in PH. Conclusion: This study provides novel evidence that endothelial Cav-1-TRPV4 signaling lowers PAP and is impaired in PH. Inhibiting NOX1 or iNOS activity, or lowering endothelial PN levels may represent a novel strategy for restoring TRPV4 EC channel activity, vasodilation, and PAP.

scholarly journals Analysis of responses to the TRPV4 agonist GSK1016790A in the pulmonary vascular bed of the intact-chest rat

2014 ◽  
Vol 306 (1) ◽  
pp. H33-H40 ◽  
Author(s):  
Edward A. Pankey ◽  
Andrea Zsombok ◽  
George F. Lasker ◽  
Philip J. Kadowitz
Keyword(s):  
Arterial Pressure ◽  
Transient Receptor Potential ◽  
Pulmonary Arterial Pressure ◽  
Systemic Arterial Pressure ◽  
Transient Receptor Potential Vanilloid ◽  
Vascular Bed ◽  
Pulmonary Arterial ◽  
Vascular Beds ◽  
Dose Dependent ◽  
Pulmonary Vascular Bed

The transient receptor potential vanilloid 4 (TRPV4) channel is a nonselective cation channel expressed on many cell types, including the vascular endothelium and smooth muscle cells. TRPV4 channels play a role in regulating vasomotor tone and capillary permeability. The present study was undertaken to investigate responses to the TRPV4 agonist GSK101790A on the pulmonary and systemic vascular beds in the rat. Intravenous injection of GSK1016790A at doses of 2–10 μg/kg produced dose-dependent decreases in systemic arterial pressure, small decreases in pulmonary arterial pressure, and small increases in cardiac output, and responses were not altered by the cyclooxygenase inhibitor meclofenamate or the cytochrome P-450 inhibitor miconazole. Injection of GSK1016790A at a dose of 12 μg/kg iv produced cardiovascular collapse that was reversible in some animals. GSK1016790A produced dose-related decreases in pulmonary and systemic arterial pressure when baseline tone in the pulmonary vascular bed was increased with U-46619. After treatment with the nitric oxide synthase (NOS) inhibitor N-nitro-l-arginine methyl ester, GSK1016790A produced larger decreases in systemic arterial pressure and dose-dependent increases in pulmonary arterial pressure followed by a small decrease. These results demonstrate that GSK1016790A has vasodilator activity in pulmonary and systemic vascular beds and that when NOS is inhibited, GSK1016790A produced pulmonary vasoconstrictor responses that were attenuated by the L-type Ca2+ channel antagonist isradipine. The presence of TRPV4 immunoreactivity was observed in small pulmonary arteries and airways. The present data indicate that responses to TRPV4 are modulated differently by NOS in pulmonary and systemic vascular beds and are attenuated by the TRPV4 antagonist GSK2193874.

scholarly journals Exposure of Stored Packed Erythrocytes to Nitric Oxide Prevents Transfusion-associated Pulmonary Hypertension

2016 ◽  
Vol 125 (5) ◽  
pp. 952-963 ◽  
Author(s):  
Stefan Muenster ◽  
Arkadi Beloiartsev ◽  
Binglan Yu ◽  
E Du ◽  
Sabia Abidi ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Erythrocyte Deformability ◽  
Pulmonary Vasculature ◽  
Prolonged Storage ◽  
Systemic Hemodynamic ◽  
Promising Therapeutic Approach ◽  
Erythrocyte Survival ◽  
Pulmonary Arterial

Abstract Background Transfusion of packed erythrocytes stored for a long duration is associated with increased pulmonary arterial pressure and vascular resistance. Prolonged storage decreases erythrocyte deformability, and older erythrocytes are rapidly removed from the circulation after transfusion. The authors studied whether treating stored packed ovine erythrocytes with NO before transfusion could prevent pulmonary vasoconstriction, enhance erythrocyte deformability, and prolong erythrocyte survival after transfusion. Methods Ovine leukoreduced packed erythrocytes were treated before transfusion with either NO gas or a short-lived NO donor. Sheep were transfused with autologous packed erythrocytes, which were stored at 4°C for either 2 (“fresh blood”) or 40 days (“stored blood”). Pulmonary and systemic hemodynamic parameters were monitored before, during, and after transfusion. Transfused erythrocytes were labeled with biotin to measure their circulating lifespan. Erythrocyte deformability was assessed before and after NO treatment using a microfluidic device. Results NO treatment improved the deformability of stored erythrocytes and increased the number of stored erythrocytes circulating at 1 and 24 h after transfusion. NO treatment prevented transfusion-associated pulmonary hypertension (mean pulmonary arterial pressure at 30 min of 21 ± 1 vs. 15 ± 1 mmHg in control and NO–treated packed erythrocytes, P < 0.0001). Washing stored packed erythrocytes before transfusion did not prevent pulmonary hypertension. Conclusions NO treatment of stored packed erythrocytes before transfusion oxidizes cell-free oxyhemoglobin to methemoglobin, prevents subsequent NO scavenging in the pulmonary vasculature, and limits pulmonary hypertension. NO treatment increases erythrocyte deformability and erythrocyte survival after transfusion. NO treatment might provide a promising therapeutic approach to prevent pulmonary hypertension and extend erythrocyte survival.

Protamine sulfate causes pulmonary hypertension and edema in isolated rat lungs

1987 ◽  
Vol 62 (4) ◽  
pp. 1363-1367 ◽  
Author(s):  
R. P. Fairman ◽  
C. N. Sessler ◽  
M. Bierman ◽  
F. L. Glauser
Keyword(s):  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Weight Ratio ◽  
Dry Weight ◽  
Protamine Sulfate ◽  
Pulmonary Vasculature ◽  
Lung Weight ◽  
Control Value ◽  
Pulmonary Arterial ◽  
Vascular Beds

The polycation protamine sulfate increases microvascular permeability in the kidney by reducing glomerular charge. We have exposed the pulmonary vasculature to protamine sulfate to determine whether electrical charges play a role in protein permeability in lung vascular beds. In anephric rats, protamine sulfate increased hematocrit approximately 25%. With protamine sulfate doses of 0.08 and 0.04 mg/g body wt, lung blood-free wet-to-dry weight ratios were increased (5.24 +/- 0.8 and 4.89 +/- 0.7) compared with control (3.85 +/- 0.3) (P less than 0.05). In isolated, ventilated, and perfused lungs 0.04 mg/g body wt protamine sulfate increased pulmonary arterial pressure from 5.2 +/- 1.4 to 16.3 +/- 3.9 mmHg (P less than 0.01). These lungs gained weight and lung wet-to-dry weight ratios were significantly increased (15.33 +/- 4.26 compared with 6.04 +/- 0.24 for control lungs). Poly-L-lysine, another polycation, also caused significant increases in pulmonary arterial pressure, lung weight, and lung wet-to-dry weight ratios. The addition of diphenhydramine to the perfusate 10 min before the addition of protamine sulfate did not prevent these changes. Heparin (90 U/mg protamine sulfate) reversed the abnormalities. Pulmonary arterial pressure (7.0 +/- 1.1 mmHg) was not significantly different from the control value, lung weight did not increase, and the lung wet-to-dry weight ratio was 6.24 +/- 0.23 (P greater than 0.05). We conclude that polycations have a significant effect on pulmonary vascular resistance and perhaps on permeability.

Inhalation of the ETAreceptor antagonist LU-135252 selectively attenuates hypoxic pulmonary vasoconstriction

2008 ◽  
Vol 294 (2) ◽  
pp. R601-R605 ◽  
Author(s):  
Bodil Petersen ◽  
Maria Deja ◽  
Roland Bartholdy ◽  
Bernd Donaubauer ◽  
Sven Laudi ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Receptor Antagonist ◽  
Experimental Model ◽  
Pulmonary Arterial Pressure ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Vasculature ◽  
Mean Pulmonary Arterial Pressure ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Arterial ◽  
To Receive

Endogenous endothelin (ET)-1 modulates hypoxic pulmonary vasoconstriction (HPV). Accordingly, intravenously applied ETAreceptor antagonists reduce HPV, but this is accompanied by systemic vasodilation. We hypothesized that inhalation of an ETAreceptor antagonist might act selectively on the pulmonary vasculature and investigated the effects of aerosolized LU-135252 in an experimental model of HPV. Sixteen piglets (weight: 25 ± 1 kg) were anesthetized and mechanically ventilated at an inspiratory oxygen fraction (FiO2) of 0.3. After 1 h of hypoxia at FiO20.15, animals were randomly assigned either to receive aerosolized LU-135252 as bolus (0.3 mg/kg for 20 min; n = 8, LU group), or to receive aerosolized saline ( n = 8, controls). In all animals, hypoxia significantly increased mean pulmonary arterial pressure (32 ± 1 vs. 23 ± 1 mmHg; P < 0.01; means ± SE) and increased arterial plasma ET-1 (0.52 ± 0.04 vs. 0.37 ± 0.05 fmol/ml; P < 0.01) compared with mild hyperoxia at FiO20.3. Inhalation of LU-135252 induced a significant and sustained decrease in mean pulmonary arterial pressure compared with controls (LU group: 27 ± 1 mmHg; controls: 32 ± 1 mmHg; values at 4 h of hypoxia; P < 0.01). In parallel, mean systemic arterial pressure and cardiac output remained stable and were not significantly different from control values. Consequently, in our experimental model of HPV, the inhaled ETAreceptor antagonist LU-135252 induced selective pulmonary vasodilation without adverse systemic hemodynamic effects.

scholarly journals Low-dose sodium nitrite vasodilates hypoxic human pulmonary vasculature by a means that is not dependent on a simultaneous elevation in plasma nitrite

2010 ◽  
Vol 298 (2) ◽  
pp. H331-H339 ◽  
Author(s):  
Thomas E. Ingram ◽  
Andrew G. Pinder ◽  
Damian M. Bailey ◽  
Alan G. Fraser ◽  
Philip E. James
Keyword(s):  
Blood Flow ◽  
Arterial Pressure ◽  
Sodium Nitrite ◽  
Forearm Blood Flow ◽  
Pulmonary Arterial Pressure ◽  
Venous Blood ◽  
Pulmonary Vasculature ◽  
Pulmonary Arterial ◽  
Clearance Kinetics ◽  
Plasma Nitrite

Inorganic nitrite has recently been recognized to possess vascular activity that is enhanced in hypoxia. This has been demonstrated in humans in the forearm vascular bed. In animal models nitrite reduces pulmonary vascular resistance, but its effects upon the pulmonary circulation of humans have not yet been demonstrated. This paradigm is of particular interest mechanistically since the pulmonary vasculature is known to behave differently to the systemic. To investigate, 18 healthy volunteers were studied in a hypoxic chamber (inspired oxygen, 12%) or while breathing room air. Each received an infusion of sodium nitrite (1 μmol/min) or 0.9% saline. Three protocols were performed: nitrite/hypoxia ( n = 12), saline/hypoxia ( n = 6), and nitrite/normoxia ( n = 6). Venous blood was sampled for plasma nitrite, forearm blood flow was measured by strain-gauge plethysmography, and pulmonary arterial pressure was measured by transthoracic echocardiography. Plasma nitrite doubled and clearance kinetics were similar whether nitrite was infused in hypoxia or normoxia. During hypoxia, nitrite increased forearm blood flow (+36%, P < 0.001) and reduced three separate indirect indexes of pulmonary arterial pressure by 16%, 12%, and 17% ( P < 0.01). Pulmonary, but not systemic, arterial effects persisted 1 h after stopping the infusion, at a time when plasma nitrite had returned to baseline. No effects were observed during normoxia. Therefore, in hypoxic but not normoxic subjects, sodium nitrite causes arterial and pulmonary vasodilatation. In addition, hypoxia-induced pulmonary vasoconstriction was attenuated for a prolonged period and not dependent on a simultaneous elevation of plasma nitrite. This finding is consistent with the direct extravascular metabolism of nitrite to nitric oxide to effect hypoxia-associated bioactivity.

Atrial natriuretic peptide lowers pulmonary arterial pressure in hypoxia-adapted rats

1988 ◽  
Vol 65 (4) ◽  
pp. 1729-1735 ◽  
Author(s):  
H. K. Jin ◽  
R. H. Yang ◽  
R. M. Thornton ◽  
Y. F. Chen ◽  
R. Jackson ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Pulmonary Arterial Pressure ◽  
Pulmonary Vasculature ◽  
Vasodilator Effect ◽  
Pulmonary Arterial ◽  
Air Control ◽  
Atrial Natriuretic

To test the hypothesis that atrial natriuretic peptide (ANP) has a direct vasodilator effect on the pulmonary vasculature that is enhanced in hypoxia-induced pulmonary hypertension in the rat, we determined the effects of ANP on mean pulmonary (MPAP) and systemic arterial pressure (MSAP) in intact conscious Sprague-Dawley rats exposed to 10% O2 or room air for 4 wk. Catheters were placed in the pulmonary artery through the right jugular vein by means of a closed-chest technique. MPAP and MSAP were monitored before and after intravenous injections of graded doses of ANP. ANP produced dose-related decreases in MPAP that were greater in the hypoxic group than in air controls. There were no significant between-group differences in the systemic depressor responses to ANP or in the ANP-induced reduction in cardiac output. ANP lowered MPAP significantly in isolated perfused lungs from both hypoxia-adapted and air control rats, and this effect was significantly greater in the hypoxic than the air control lungs. These data indicate that ANP lowers pulmonary arterial pressure in rats with hypoxia-induced pulmonary hypertension, mainly by a direct vasodilator effect on the pulmonary vasculature.

scholarly journals Regulation of Pulmonary Arterial Pressure by Endothelial Pannexin1–TRPV4 Channel Signaling

2021 ◽  
Vol 35 (S1) ◽  
Author(s):  
Zdravka Daneva ◽  
Matteo Ottolini ◽  
Yen‐Lin Chen ◽  
Brant Isakson ◽  
Swapnil Sonkusare
Keyword(s):  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Pulmonary Arterial ◽  
Trpv4 Channel
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