Endocannabinoid anandamide mediates hypoxic pulmonary vasoconstriction.
Ontology highlight
ABSTRACT:
SUBMITTER: Wenzel D
PROVIDER: S-EPMC3831960 | biostudies-literature | 2013 Nov
REPOSITORIES: biostudies-literature
Publications
Endocannabinoid anandamide mediates hypoxic pulmonary vasoconstriction.
Wenzel Daniela D Matthey Michaela M Bindila Laura L Lerner Raissa R Lutz Beat B Zimmer Andreas A Fleischmann Bernd K BK
Proceedings of the National Academy of Sciences of the United States of America 20131028 46
Endocannabinoids are important regulators of organ homeostasis. Although their role in systemic vasculature has been extensively studied, their impact on pulmonary vessels remains less clear. Herein, we show that the endocannabinoid anandamide (AEA) is a key mediator of hypoxic pulmonary vasoconstriction (HPV) via fatty acid amide hydrolase (FAAH)-dependent metabolites. This is underscored by the prominent vasoconstrictive effect of AEA on pulmonary arteries and strongly reduced HPV in FAAH(-/-) ...[more]
Similar Datasets
Project description:Hypoxia triggers pulmonary vasoconstriction, however induces relaxation of systemic arteries such as femoral arteries. Mitochondria are functionally and structurally heterogeneous between different cell types. The aim of this study was to reveal whether mitochondrial heterogeneity controls the distinct responses of pulmonary versus systemic artery smooth muscle cells to hypoxia. Intact mitochondria were transplanted into Sprague-Dawley rat pulmonary artery smooth muscle cells in culture and pulmonary arteries in vitro. Mitochondria retained functional after transplantation. The cross transplantation of mitochondria between pulmonary and femoral artery smooth muscle cells reversed acute hypoxia-induced alterations in cell membrane potential, [Ca2+]i signaling in smooth muscle cells and constriction or relaxation of arteries. Furthermore, the high or low amount of reactive oxygen species generation from mitochondria and their divergent (dis-)abilities in activating extracellular Ca2+-sensing receptor in smooth muscle cells were found to cause cell membrane potential depolarization, [Ca2+]i elevation and constriction of pulmonary arteries versus cell membrane potential hyperpolarization, [Ca2+]i decline and relaxation of femoral arteries in response to hypoxia, respectively. Our findings suggest that mitochondria necessarily determine the behaviors of vascular smooth muscle cells in response to hypoxia.
| S-EPMC5058756 | biostudies-literature
Project description:Hypoxic pulmonary vasoconstriction (HPV) optimizes pulmonary ventilation-perfusion matching in regional hypoxia, but promotes pulmonary hypertension in global hypoxia. Ventilation-perfusion mismatch is a major cause of hypoxemia in cystic fibrosis. We hypothesized that cystic fibrosis transmembrane conductance regulator (CFTR) may be critical in HPV, potentially by modulating the response to sphingolipids as mediators of HPV. HPV and ventilation-perfusion mismatch were analyzed in isolated mouse lungs or in vivo. Ca(2+) mobilization and transient receptor potential canonical 6 (TRPC6) translocation were studied in human pulmonary (PASMCs) or coronary (CASMCs) artery smooth muscle cells. CFTR inhibition or deficiency diminished HPV and aggravated ventilation-perfusion mismatch. In PASMCs, hypoxia caused CFTR to interact with TRPC6, whereas CFTR inhibition attenuated hypoxia-induced TRPC6 translocation to caveolae and Ca(2+) mobilization. Ca(2+) mobilization by sphingosine-1-phosphate (S1P) was also attenuated by CFTR inhibition in PASMCs, but amplified in CASMCs. Inhibition of neutral sphingomyelinase (nSMase) blocked HPV, whereas exogenous nSMase caused TRPC6 translocation and vasoconstriction that were blocked by CFTR inhibition. nSMase- and hypoxia-induced vasoconstriction, yet not TRPC6 translocation, were blocked by inhibition or deficiency of sphingosine kinase 1 (SphK1) or antagonism of S1P receptors 2 and 4 (S1P2/4). S1P and nSMase had synergistic effects on pulmonary vasoconstriction that involved TRPC6, phospholipase C, and rho kinase. Our findings demonstrate a central role of CFTR and sphingolipids in HPV. Upon hypoxia, nSMase triggers TRPC6 translocation, which requires its interaction with CFTR. Concomitant SphK1-dependent formation of S1P and activation of S1P2/4 result in phospholipase C-mediated TRPC6 and rho kinase activation, which conjointly trigger vasoconstriction.
| S-EPMC4386337 | biostudies-literature
Project description:BackgroundHypoxic pulmonary vasoconstriction (HPV) optimizes the match between ventilation and perfusion in the lung by reducing blood flow to poorly ventilated regions. Sepsis and endotoxemia impair HPV. We previously showed that nitric oxide synthase 2 (NOS2) is required, but not sufficient, for the effect of endotoxin on HPV. The aim of the current study was to identify additional factors that might contribute to the impairment of HPV during endotoxemia.MethodsGene expression profiling was determined using pulmonary tissues from NOS2-deficient (NOS2-/-) and wild-type mice subjected to endotoxin or saline challenge (control). HPV was accessed as the percentage increase in left pulmonary vascular resistance (LPVR) in response to left main bronchus occlusion (LMBO) in wild-type mice.ResultsAmong the 22,690 genes analyzed, endotoxin induced a greater than three-fold increase in 59 and 154 genes in the lungs of wild-type and NOS2-/- mice, respectively. Of all the genes induced by endotoxin in wild-type mice, arginase 1 (Arg1) showed the greatest increase (16.3-fold compared to saline treated wild-type mice). In contrast, endotoxin did not increase expression of Arg1 in NOS2-/- mice. There was no difference in the endotoxin-induced expression of Arg2 between wild-type and NOS2-deficient mice. We investigated the role of arginase in HPV by treating the mice with normal saline or the arginase inhibitor Nω-hydroxy-nor-L-arginine (norNOHA). In control mice (in the absence of endotoxin) treated with normal saline, HPV was intact as determined by profound LMBO-induced increase in LPVR (121 ± 22% from baseline). During endotoxemia and treatment with normal saline, HPV was impaired compared to normal saline treated control mice (33 ± 9% vs. 121 ± 22%, P < 0.05). HPV was restored in endotoxin-exposed mice after treatment with the arginase inhibitor norNOHA as shown by the comparison to endotoxemic mice treated with normal saline (113 ± 29% vs, 33 ± 9%, P < 0.05) and to control mice treated with normal saline (113 ± 29% vs, 121 ± 22%, P = 0.97).ConclusionsThe results of this study suggest that endotoxemia induces Arg1 and that arginase contributes to the endotoxin-induced impairment of HPV in mice.
| S-EPMC6547543 | biostudies-literature
Project description:Hypoxic pulmonary vasoconstriction (HPV) is a homeostatic mechanism that is intrinsic to the pulmonary vasculature. Intrapulmonary arteries constrict in response to alveolar hypoxia, diverting blood to better-oxygenated lung segments, thereby optimizing ventilation/perfusion matching and systemic oxygen delivery. In response to alveolar hypoxia, a mitochondrial sensor dynamically changes reactive oxygen species and redox couples in pulmonary artery smooth muscle cells (PASMC). This inhibits potassium channels, depolarizes PASMC, activates voltage-gated calcium channels, and increases cytosolic calcium, causing vasoconstriction. Sustained hypoxia activates rho kinase, reinforcing vasoconstriction, and hypoxia-inducible factor (HIF)-1α, leading to adverse pulmonary vascular remodeling and pulmonary hypertension (PH). In the nonventilated fetal lung, HPV diverts blood to the systemic vasculature. After birth, HPV commonly occurs as a localized homeostatic response to focal pneumonia or atelectasis, which optimizes systemic Po2 without altering pulmonary artery pressure (PAP). In single-lung anesthesia, HPV reduces blood flow to the nonventilated lung, thereby facilitating thoracic surgery. At altitude, global hypoxia causes diffuse HPV, increases PAP, and initiates PH. Exaggerated or heterogeneous HPV contributes to high-altitude pulmonary edema. Conversely, impaired HPV, whether due to disease (eg, COPD, sepsis) or vasodilator drugs, promotes systemic hypoxemia. Genetic and epigenetic abnormalities of this oxygen-sensing pathway can trigger normoxic activation of HIF-1α and can promote abnormal metabolism and cell proliferation. The resulting pseudohypoxic state underlies the Warburg metabolic shift and contributes to the neoplasia-like phenotype of PH. HPV and oxygen sensing are important in human health and disease.
| S-EPMC5310129 | biostudies-literature
Project description:Context:Skeletal muscle endocannabinoids and sphingolipids (particularly sphingomyelins) are inversely associated with sleeping energy expenditure (SLEEP) in humans. The endocannabinoid system may increase sphingolipid synthesis via cannabinoid receptor-1. Objective:To investigate in human skeletal muscle whether endocannabinoids are responsible for the effect of sphingomyelins on SLEEP. Design:Muscle endocannabinoid [anandamide (AEA), 2-arachidonoylglycerol (2-AG)], endocannabinoid congeners [oleoylethanolamide (OEA), palmitoylethanolamide (PEA)], and sphingomyelin content were measured with liquid chromatography/mass spectrometry. SLEEP was assessed in a whole-room indirect calorimeter. Mediation analyses tested whether the inverse associations between sphingomyelins and SLEEP depended on endocannabinoids and endocannabinoid-related OEA and PEA. Setting:Inpatient study. Participants:Fifty-three Native Americans who are overweight. Main Outcome Measure:SLEEP. Results:AEA (r = 0.45, P = 0.001), 2-AG (r = 0.47, P = 0.0004), OEA (r = 0.27, P = 0.05), and PEA (r = 0.53, P < 0.0001) concentrations were associated with the total sphingomyelin content. AEA, OEA, and PEA correlated with specific sphingomyelins (SM18:1/23:0, SM18:1/23:1, and SM18:1/26:1) previously reported to be determinants of SLEEP in Native Americans (all r > 0.31, all P < 0.03). Up to half of the negative effect of these specific sphingomyelins on SLEEP was accounted for by AEA (all P < 0.04), rendering the direct effect by sphingomyelins per se on SLEEP negligible (P > 0.05). Conclusions:In skeletal muscle, AEA is responsible for the sphingomyelin effect on SLEEP, indicating that endocannabinoids and sphingomyelins may jointly reduce human whole-body energy metabolism.
| S-EPMC6179180 | biostudies-literature
Project description:AimsHypoxic pulmonary vasoconstriction (HPV) redistributes blood flow from poorly ventilated to better aerated areas in the lung, thereby optimizing ventilation-perfusion ratio (V/Q). Pulmonary artery smooth muscle cell (PASMC) contraction in response to hypoxia is triggered by Ca2+ influx via transient receptor potential canonical 6 (TRPC6) cation channels that have translocated to caveolae in the plasma membrane. Since phosphatase and tensin homolog (PTEN) was suggested to regulate TRPC6 in endothelial cells, we aimed to define its role in the hypoxic response of PASMCs and as a putative mediator of HPV.Methods and resultsIn isolated perfused mouse lungs, smooth muscle specific PTEN deficiency attenuated pulmonary vasoconstriction in response to hypoxia but not to angiotensin II (Ang II). Analogously, siRNA-mediated knock down of PTEN in human PASMC inhibited the hypoxia-induced increase in cytosolic Ca2+ concentration ([Ca2+]i). Co-immunoprecipitation and proximity ligation assays revealed increased interaction of PTEN with TRPC6 in human PASMC and murine lungs in response to hypoxia. In hypoxic PASMC, both PTEN and TRPC6 translocated to caveolae, and this response was blocked by pharmacological inhibition of Rho-associated protein kinase (ROCK) which in parallel prevented PTEN-TRPC6 interaction, hypoxia-induced [Ca2+]i increase, and HPV in PASMC and murine lungs, respectively.ConclusionOur data indicate a novel interplay between ROCK and [Ca2+]i signalling in HPV via PTEN, in that ROCK mediates interaction of PTEN and TRPC6 which then conjointly translocate to caveolae allowing for Ca2+ influx into and subsequent contraction of PASMC.
| S-EPMC5852630 | biostudies-literature
Project description:AimsHypoxic pulmonary vasoconstriction (HPV) is a physiological response to alveolar hypoxia that diverts blood flow from poorly ventilated to better aerated lung areas to optimize ventilation-perfusion matching. Yet, the exact sensory and signalling mechanisms by which hypoxia triggers pulmonary vasoconstriction remain incompletely understood. Recently, ATP release via pannexin 1 (Panx1) and subsequent signalling via purinergic P2Y receptors has been identified as regulator of vasoconstriction in systemic arterioles. Here, we probed for the role of Panx1-mediated ATP release in HPV and chronic hypoxic pulmonary hypertension (PH).Methods and resultsPharmacological inhibition of Panx1 by probenecid, spironolactone, the Panx1 specific inhibitory peptide (10Panx1), and genetic deletion of Panx1 specifically in smooth muscle attenuated HPV in isolated perfused mouse lungs. In pulmonary artery smooth muscle cells (PASMCs), both spironolactone and 10Panx1 attenuated the increase in intracellular Ca2+ concentration ([Ca2+]i) in response to hypoxia. Yet, genetic deletion of Panx1 in either endothelial or smooth muscle cells did not prevent the development of PH in mice. Unexpectedly, ATP release in response to hypoxia was not detectable in PASMC, and inhibition of purinergic receptors or ATP degradation by ATPase failed to attenuate HPV. Rather, transient receptor potential vanilloid 4 (TRPV4) antagonism and Panx1 inhibition inhibited the hypoxia-induced [Ca2+]i increase in PASMC in an additive manner, suggesting that Panx1 regulates [Ca2+]i independently of the ATP-P2Y-TRPV4 pathway. In line with this notion, Panx1 overexpression increased the [Ca2+]i response to hypoxia in HeLa cells.ConclusionIn the present study, we identify Panx1 as novel regulator of HPV. Yet, the role of Panx1 in HPV was not attributable to ATP release and downstream signalling via P2Y receptors or TRPV4 activation, but relates to a role of Panx1 as direct or indirect modulator of the PASMC Ca2+ response to hypoxia. Panx1 did not affect the development of chronic hypoxic PH.
| S-EPMC9612799 | biostudies-literature
Project description:Acute respiratory distress syndrome (ARDS) is a serious complication of severe systemic or local pulmonary inflammation, such as caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. ARDS is characterised by diffuse alveolar damage that leads to protein-rich pulmonary oedema, local alveolar hypoventilation and atelectasis. Inadequate perfusion of these areas is the main cause of hypoxaemia in ARDS. High perfusion in relation to ventilation (V/Q<1) and shunting (V/Q=0) is not only caused by impaired hypoxic pulmonary vasoconstriction but also redistribution of perfusion from obstructed lung vessels. Rebalancing the pulmonary vascular tone is a therapeutic challenge. Previous clinical trials on inhaled vasodilators (nitric oxide and prostacyclin) to enhance perfusion to high V/Q areas showed beneficial effects on hypoxaemia but not on mortality. However, specific patient populations with pulmonary hypertension may profit from treatment with inhaled vasodilators. Novel treatment targets to decrease perfusion in low V/Q areas include epoxyeicosatrienoic acids and specific leukotriene receptors. Still, lung protective ventilation and prone positioning are the best available standard of care. This review focuses on disturbed perfusion in ARDS and aims to provide basic scientists and clinicians with an overview of the vascular alterations and mechanisms of V/Q mismatch, current therapeutic strategies, and experimental approaches.
| S-EPMC9489056 | biostudies-literature
Project description:Hypoxic pulmonary vasoconstriction (HPV) is a physiological mechanism by which pulmonary arteries constrict in hypoxic lung areas in order to redirect blood flow to areas with greater oxygen supply. Both oxygen sensing and the contractile response are thought to be intrinsic to pulmonary arterial smooth muscle cells. Here we speculated that the ideal site for oxygen sensing might instead be at the alveolocapillary level, with subsequent retrograde propagation to upstream arterioles via connexin 40 (Cx40) endothelial gap junctions. HPV was largely attenuated by Cx40-specific and nonspecific gap junction uncouplers in the lungs of wild-type mice and in lungs from mice lacking Cx40 (Cx40-/-). In vivo, hypoxemia was more severe in Cx40-/- mice than in wild-type mice. Real-time fluorescence imaging revealed that hypoxia caused endothelial membrane depolarization in alveolar capillaries that propagated to upstream arterioles in wild-type, but not Cx40-/-, mice. Transformation of endothelial depolarization into vasoconstriction involved endothelial voltage-dependent α1G subtype Ca2+ channels, cytosolic phospholipase A2, and epoxyeicosatrienoic acids. Based on these data, we propose that HPV originates at the alveolocapillary level, from which the hypoxic signal is propagated as endothelial membrane depolarization to upstream arterioles in a Cx40-dependent manner.
| S-EPMC3484430 | biostudies-literature
Project description:RationaleNeonatal chronic lung disease (CLD), caused by prolonged mechanical ventilation (MV) with O(2)-rich gas, is the most common cause of long-term hospitalization and recurrent respiratory illness in extremely premature infants. Recurrent episodes of hypoxemia and associated ventilator adjustments often lead to worsening CLD. The mechanism that causes these hypoxemic episodes is unknown. Hypoxic pulmonary vasoconstriction (HPV), which is partially controlled by O(2)-sensitive voltage-gated potassium (K(v)) channels, is an important adaptive response to local hypoxia that helps to match perfusion and ventilation in the lung.ObjectivesTo test the hypothesis that chronic lung injury (CLI) impairs HPV.MethodsWe studied preterm lambs that had MV with O(2)-rich gas for 3 weeks and newborn rats that breathed 95%-O(2) for 2 weeks, both of which resulted in airspace enlargement and pulmonary vascular changes consistent with CLD.Measurements and main resultsHPV was attenuated in preterm lambs with CLI after 2 weeks of MV and in newborn rats with CLI after 2 weeks of hyperoxia. HPV and constriction to the K(v)1.x-specific inhibitor, correolide, were preferentially blunted in excised distal pulmonary arteries (dPAs) from hyperoxic rats, whose dPAs exhibited decreased K(v)1.5 and K(v)2.1 mRNA and K(+) current. Intrapulmonary gene transfer of K(v)1.5, encoding the ion channel that is thought to trigger HPV, increased O(2)-sensitive K(+) current in cultured smooth muscle cells from rat dPAs, and restored HPV in hyperoxic rats.ConclusionsReduced expression/activity of O(2)-sensitive K(v) channels in dPAs contributes to blunted HPV observed in neonatal CLD.
| S-EPMC2542441 | biostudies-literature