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 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 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 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

PAF increases vascular permeability without increasing pulmonary arterial pressure in the rat

2001 ◽  
Vol 90 (1) ◽  
pp. 261-268 ◽  
Author(s):  
Leonardo C. Clavijo ◽  
Mary B. Carter ◽  
Paul J. Matheson ◽  
Mark A. Wilson ◽  
William B. Wead ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Pulmonary Edema ◽  
Pulmonary Arterial Pressure ◽  
Ex Vivo ◽  
Platelet Activating Factor ◽  
Microvascular Permeability ◽  
Blue Dye ◽  
E Coli ◽  
Pulmonary Arterial

In vivo pulmonary arterial catheterization was used to determine the mechanism by which platelet-activating factor (PAF) produces pulmonary edema in rats. PAF induces pulmonary edema by increasing pulmonary microvascular permeability (PMP) without changing the pulmonary pressure gradient. Rats were cannulated for measurement of pulmonary arterial pressure (Ppa) and mean arterial pressure. PMP was determined by using either in vivo fluorescent videomicroscopy or the ex vivo Evans blue dye technique. WEB 2086 was administered intravenously (IV) to antagonize specific PAF effects. Three experiments were performed: 1) IV PAF, 2) topical PAF, and 3) Escherichia coli bacteremia. IV PAF induced systemic hypotension with a decrease in Ppa. PMP increased after IV PAF in a dose-related manner. Topical PAF increased PMP but decreased Ppa only at high doses. Both PMP (88 ± 5%) and Ppa (50 ± 3%) increased during E. coli bacteremia. PAF-receptor blockade prevents changes in Ppa and PMP after both topical PAF and E. coli bacteremia. PAF, which has been shown to mediate pulmonary edema in prior studies, appears to act in the lung by primarily increasing microvascular permeability. The presence of PAF might be prerequisite for pulmonary vascular constriction during gram-negative bacteremia.

scholarly journals Evaluation of the genetic relationship between high elevation pulmonary arterial pressure with moderate elevation with feedlot and carcass performance

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. S98-S102
Author(s):  
Emma A Briggs ◽  
Richard Mark Enns ◽  
Milton G Thomas ◽  
Tim N Holt ◽  
Scott E Speidel
Keyword(s):  
Arterial Pressure ◽  
Genetic Relationship ◽  
Pulmonary Arterial Pressure ◽  
High Elevation ◽  
Pulmonary Arterial ◽  
Carcass Performance ◽  
Moderate Elevation

scholarly journals 275 Phenotypic relationships between heart score and feed efficiency, carcass, and pulmonary arterial pressure traits

2020 ◽  
Vol 98 (Supplement_4) ◽  
pp. 204-205
Author(s):  
Kathryn R Heffernan ◽  
Scott Speidel ◽  
Milt Thomas ◽  
Mark Enns ◽  
Tim Holt
Keyword(s):  
Arterial Pressure ◽  
Feed Efficiency ◽  
Pulmonary Arterial Pressure ◽  
Carcass Traits ◽  
Multiple Linear Regression Model ◽  
Strong Relationship ◽  
Fixed Effect ◽  
Heart Score ◽  
Important Relationship ◽  
Pulmonary Arterial

Abstract Pulmonary hypertension (PH) can lead to premature mortality in fed cattle and is often called Feedlot Heart Disease (FHD). To date, pulmonary arterial pressure (PAP) has been the only indicator trait of PH that has been evaluated. The objective of this study was to evaluate relationships between heart score (using heart score as a phenotype for PH) and PAP, carcass, and feed efficiency traits in fattening Angus steers. Our hypothesis was that feed efficiency and carcass traits, along with PAP, would demonstrate a strong relationship with heart score. Feed efficiency, carcass, PAP and heart score data from 89 Black Angus steers from Colorado State University Beef Improvement Center were collected and used for this study. Evaluations were performed using a multiple linear regression model, which included heart score as a categorical fixed effect and age as a continuous fixed effect. Least Square Means, pairwise comparisons, and ANOVA tables were constructed per trait. PAP (P < 0.001) showed an important relationship to heart score and average dry matter (P < 0.10) intake approached importance to heart score. In general, feed efficiency and carcass traits decreased as heart score increased, but PAP was the only trait with a strong relationship to heart score (P < 0.05). This led us to reject our hypothesis.

scholarly journals 265 Evaluation of the genetic relationship amongst high elevation pulmonary arterial pressure, feedlot and carcass performance traits

2020 ◽  
Vol 98 (Supplement_4) ◽  
pp. 197-197
Author(s):  
Emma A Briggs ◽  
Scott Speidel ◽  
Mark Enns ◽  
Milt Thomas ◽  
Tim Holt
Keyword(s):  
Arterial Pressure ◽  
Genetic Relationship ◽  
Feed Intake ◽  
Pulmonary Arterial Pressure ◽  
Carcass Traits ◽  
Genetic Correlations ◽  
High Elevation ◽  
Pulmonary Arterial ◽  
Carcass Performance ◽  
Moderate Elevation

Abstract The objective of the study was to evaluate if a genetic relationship exists between pulmonary arterial pressure (PAP) measured at high elevation with traits associated with moderate elevation feedlot and carcass traits. For this analysis, PAP, feed intake, and carcass data were taken from 6,898, 558, and 1,627 animals, respectively. At an elevation of 2,115 m, PAP measurements were collected, then a selective group of steers was relocated to a moderate elevation feedlot (1,500 m) where feed intake data were collected. Genetic relationships were evaluated with 5-trait animal models using REML statistical analysis. For all traits in the analysis, fixed effects and contemporary groups were assigned as well as a direct genetic random effect. For weaning weight, a maternal permanent environmental effect was applied in the analysis. For PAP, the heritability estimate was 0.29 ± 0.03. Genetic correlations between PAP with feedlot traits was positive, with estimates of 0.34 ± 0.20 (average dry matter intake) and 0.05 ± 17 (average daily gain). The strongest genetic correlation between PAP and carcass performance traits were those of rib eye area (-0.30 ± 0.12) and calculated yield grade (0.29 ± 0.13). Genetic correlations between PAP and marbling score, back fat, or hot carcass weight were 0.00 ± 0.13, -0.07 ± 0.13, and 0.14 ± 0.10, respectively. These results suggest a favorable genetic relationship exists between PAP with feedlot and carcass traits.

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