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Pathways involved in hypoxic pulmonary vasoconstriction. Acute hypoxia results in an increase of intracellular calcium in pulmonary arterial smooth muscle cells and thus contraction. This increase in calcium is achieved by inflow of extracellular calcium through plasmalemnal calcium channels and release of intracellularly stored calcium. Hypoxic effects could be mediated or modulated by a decrease (left side) or increase (right side) of reactive oxygen species (ROS). NADPH: reduced nicotinamide adenine dinucleotide phosphate; NSCC: nonspecific cation channels; TRP: transient receptor potential; NADH: reduced nicotinamide adenine dinucleotide; NAD: nicotinamide adenine dinulceotide; NADP: nicotinamide adenine dinucleotide phosphate; CCE: capacitative calcium entry; ATP: adenosine triphosphate; IP 3 : inositol triphosphate; cADPR: cyclic ADP-ribose; SR: sarcoplasmatic reticulum.
Source publication
Hypoxic pulmonary vasoconstriction (HPV), also known as the von Euler-Liljestrand mechanism, is a physiological response to alveolar hypoxia which distributes pulmonary capillary blood flow to alveolar areas of high oxygen partial pressure. Impairment of this mechanism may result in hypoxaemia. Under conditions of chronic hypoxia generalised vasoco...
Citations
... RV systolic pressure (RVSP), a surrogate of pulmonary arterial pressure, indicated that only WT mice developed PH after chronic hypoxia (Fig. 1G). Alveolar hypoxia triggers lung vasculature remodeling, vasoconstriction, and lung inflammation, which progress to PH (28)(29)(30)(31)(32). WT mice subjected to chronic hypoxia displayed an augmented density of muscularized vessels, characterized by extensive structural alterations in the vascular wall and infiltration of macrophages and neutrophils within the lungs. ...
Pulmonary hypertension (PH) can affect both pulmonary arterial tree and cardiac function, often leading to right heart failure and death. Despite the urgency, the lack of understanding has limited the development of effective cardiac therapeutic strategies. Our research reveals that MCJ modulates mitochondrial response to chronic hypoxia. MCJ levels elevate under hypoxic conditions, as in lungs of patients affected by COPD, mice exposed to hypoxia, and myocardium from pigs subjected to right ventricular (RV) overload. The absence of MCJ preserves RV function, safeguarding against both cardiac and lung remodeling induced by chronic hypoxia. Cardiac-specific silencing is enough to protect against cardiac dysfunction despite the adverse pulmonary remodeling. Mechanistically, the absence of MCJ triggers a protective preconditioning state mediated by the ROS/mTOR/HIF-1α axis. As a result, it preserves RV systolic function following hypoxia exposure. These discoveries provide a potential avenue to alleviate chronic hypoxia-induced PH, highlighting MCJ as a promising target against this condition.
... For example, studies support a direct role for mitochondria-derived superoxide in cardiac ischemia-reperfusion injury [22], systemic hypertension [23], and angiotensin II signaling in endothelial cells [24]. Although there is considerable debate regarding the role of mitochondrial ROS (mtROS) in acute hypoxic pulmonary vasoconstriction [25,26], there is little evidence to support a direct contribution of mtROS to CH-induced PH. Furthermore, conflicting evidence exists with respect to effects of chronic in vitro hypoxia on mtROS production in human pulmonary arterial endothelial cells [12] and murine PASMCs [27], as well as effects of targeted reduction of mtROS on indices of PH in vivo [12,27]. ...
Pulmonary hypertension (PH) resulting from chronic hypoxia (CH) occurs in patients with chronic obstructive pulmonary diseases, sleep apnea, and restrictive lung diseases, as well as in residents at high altitude. Previous studies from our group and others demonstrate a detrimental role of reactive oxygen species (ROS) in the pathogenesis of CH-induced PH, although the subcellular sources of ROS are not fully understood. We hypothesized that mitochondria-derived ROS (mtROS) contribute to enhanced vasoconstrictor reactivity and PH following CH. To test the hypothesis, we exposed rats to 4 weeks of hypobaric hypoxia (PB ≈ 380 mmHg), with control rats housed in ambient air (PB ≈ 630 mmHg). Chronic oral administration of the mitochondria-targeted antioxidant MitoQ attenuated CH-induced decreases in pulmonary artery (PA) acceleration time, increases in right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary arterial remodeling. In addition, endothelium-intact PAs from CH rats exhibited a significantly greater basal tone compared to those from control animals, as was eliminated via MitoQ. CH also augmented the basal tone in endothelium-disrupted PAs, a response associated with increased mtROS production in primary PA smooth muscle cells (PASMCs) from CH rats. However, we further uncovered an effect of NO synthase inhibition with Nω–nitro-L-arginine (L-NNA) to unmask a potent endothelial vasoconstrictor influence that accentuates mtROS-dependent vasoconstriction following CH. This basal tone augmentation in the presence of L-NNA disappeared following combined endothelin A and B receptor blockade with BQ123 and BQ788. The effects of using CH to augment vasoconstriction and PASMC mtROS production in exogenous endothelin 1 (ET-1) were similarly prevented by MitoQ. We conclude that mtROS participate in the development of CH-induced PH. Furthermore, mtROS signaling in PASMCs is centrally involved in enhanced pulmonary arterial constriction following CH, a response potentiated by endogenous ET-1.
... Sleep apnea is well recognized as a cause of hypoxia and hypercarbia with subsequent hypoxic pulmonary vasoconstriction, particularly once the alveolar partial pressure for oxygen drops below a threshold of 60 mm Hg. This is known as the von Euler-Liljestrand reflex, whereby pulmonary vascular resistance is increased in regions that are hypoventilated in an attempt to avoid ventilation-perfusion mismatch [2]. ...
... Pulmonary hypertension is defined as increased pressure in the pulmonary circulation with a systolic pressure at rest of 18-25 mm Hg, diastolic pressure of 10 mm Hg and mean pulmonary artery pressure of 12-16 mm Hg at sea level, rising to 30/13 mm Hg (mean 20 mm Hg) with mild exercise. Pulmonary artery pressures rise with altitude: at 15,000 feet, normal resting pulmonary artery pressures are about 38/14 mm Hg [2,4,7]. ...
... Pulmonary hypertension is classified by the World Health Organization into five categories, according to etiology, pathophysiology or histopathology, clinical characteristics and hemodynamic profile [2][3][4]. Group 1 pulmonary hypertension, also called idiopathic pulmonary hypertension, is characterized by plexiform or plexogenic lesions as a result of angioproliferative activity of endothelial cells in tandem with hyperplasia and hypertrophy of the smooth muscles in precapillary arterioles. Pulmonary arterial hypertension requires that the left ventricular filling pressure, pulmonary capillary wedge pressure, left atrial pressure and left ventricular end-diastolic pressure be 15 mm Hg or less, and that the calculated pulmonary vascular resistance be greater than 3 Woods Units (WU), which is defined as pulmonary arterial pressure minus capillary wedge pressure divided by the cardiac output (e.g., 25 − 10/5 = 3 WU). ...
We have investigated the concurrence of sleep apnea and pulmonary hypertension in a Veteran population. We retrospectively reviewed 142 patients who underwent chest CT scans and had a dilated main pulmonary artery, defined as a width exceeding 29 mm on axial images. Approximately 40% of patients with pulmonary hypertension had associated sleep apnea. No significant difference in pulmonary artery diameters could be found between the group without sleep apnea and the group with sleep apnea (34.5 ± 4.2 mm vs. 34.7 ± 4.4 mm, p = 0.373).
... According to this mechanism, the consequence of ventilation/perfusion mismatch may divert blood flow from the hypoxic, affected pulmonary circulation to the relatively normal, unaffected circulation, reducing the extent of thrombolysis in the clot area among patients receiving systemic thrombolysis. 70,71 In addition, CDT with a multi-hole catheter directly infuses thrombolysis and provides direct contact with the thrombolytic agent to a greater surface area of thrombus. 72 As for safety outcomes, we found a statistically significant lower risk for intracerebral hemorrhage, major bleeding and blood transfusion after the acute PE episode among patients treated with CDT compared with patients treated with systemic thrombolysis. ...
Background:
Therapeutic options for intermediate- or high-risk pulmonary embolism (PE) include anticoagulation, systemic thrombolysis and catheter-directed thrombolysis (CDT); however, the role of CDT remains controversial. We sought to compare the efficacy and safety of CDT with other therapeutic options using network meta-analysis.
Methods:
We searched PubMed (MEDLINE), Embase, ClinicalTrials.gov and Cochrane Library from inception to Oct. 18, 2022. We included randomized controlled trials and observational studies that compared therapeutic options for PE, including anticoagulation, systemic thrombolysis and CDT among patients with intermediate- or high-risk PE. The efficacy outcome was in-hospital death. Safety outcomes included major bleeding, intracerebral hemorrhage and minor bleeding.
Results:
We included data from 44 studies, representing 20 006 patients. Compared with systemic thrombolysis, CDT was associated with a decreased risk of death (odd ratio [OR] 0.43, 95% confidence interval [CI] 0.32-0.57), intracerebral hemorrhage (OR 0.44, 95% CI 0.29-0.64), major bleeding (OR 0.61, 95% CI 0.53-0.70) and blood transfusion (OR 0.46, 95% CI 0.28-0.77). However, no difference in minor bleeding was observed between the 2 therapeutic options (OR 1.11, 95% CI 0.66-1.87). Compared with anticoagulation, CDT was also associated with decreased risk of death (OR 0.36, 95% CI 0.25-0.52), with no increased risk of intracerebral hemorrhage (OR 1.33, 95% CI 0.63-2.79) or major bleeding (OR 1.24, 95% CI 0.88-1.75).
Interpretation:
With moderate certainty of evidence, the risk of death and major bleeding complications was lower with CDT than with systemic thrombolysis. Compared with anticoagulation, CDT was associated with a probable lower risk of death and a similar risk of intracerebral hemorrhage, with moderate certainty of evidence. Although these findings are largely based on observational data, CDT may be considered as a first-line therapy in patients with intermediate- or high-risk PE.
Protocol registration:
PROSPERO - CRD42020182163.
... In contrast, systemic vessels, which distribute oxygen to peripheral organs, react to tissue hypoxia with vasodilation, as shown for example for smooth muscle cells from isolated cerebral arteries [7,8]. Substantial effort was undertaken to understand the underlying mechanisms of these different responses to hypoxia [1,6,9]. HPV can be detected in humans and almost all vertebrates, including mammals [10][11][12][13], birds [14], amphibia [15], reptiles [16], and even fish gills [17,18], and thus may be the consequence of an evolutionary highly conserved molecular mechanism. ...
... In addition to their function as signaling molecules in biochemical processes, high concentrations of ROS can cause cell damage. The importance of mitochondria in the detection of acute hypoxia and mitochondrial ROS as signaling molecules in pulmonary vascular cells has been known for a long time, but the primary oxygen sensing mechanism remained unclear [1,6,9,[50][51][52][53]. Moreover, it was unclear, whether an increase or decrease of ROS is involved in the acute oxygen sensing underlying HPV and how a paradoxical increase of ROS could be initiated at low levels of oxygen, the substrate for ROS generation. ...
... ROS comprise a group of highly reactive molecules including the short-lived cell membrane impermeable superoxide, which is metabolized to membrane diffusible hydrogen peroxide (H 2 O 2 ) by superoxide dismutases (SODs). Several considerations point at ROS as mediators for HPV: 1) ROS generation is fast and thus can mediate the response to acute hypoxia within seconds; and 2) mitochondrial inhibitor studies indicate relevance of ROS from complex I and/or III in acute hypoxia, although these inhibitor studies showed conflicting results with regard to a decrease or increase of ROS and complex IV inhibition (reviewed in [9]). Based on these conflicting results and further ROS measurements, two hypotheses were formulated: 1) the initial "redox hypothesis" stating that decreased oxygen levels as the substrate for ROS decrease ROS levels during hypoxia and inhibit K v channels leading to HPV; 2) a second hypothesis that proposed a paradoxical ROS increase in acute hypoxia [54,55]. ...
Acclimation to acute hypoxia through cardiorespiratory responses is mediated by specialized cells in the carotid body and pulmonary vasculature to optimize systemic arterial oxygenation and thus oxygen supply to the tissues. Acute oxygen sensing by these cells triggers hyperventilation and hypoxic pulmonary vasoconstriction which limits pulmonary blood flow through areas of low alveolar oxygen content. Oxygen sensing of acute hypoxia by specialized cells thus is a fundamental pre-requisite for aerobic life and maintains systemic oxygen supply. However, the primary oxygen sensing mechanism and the question of a common mechanism in different specialized oxygen sensing cells remains unresolved. Recent studies unraveled basic oxygen sensing mechanisms involving the mitochondrial cytochrome c oxidase subunit 4 isoform 2 that is essential for the hypoxia-induced release of mitochondrial reactive oxygen species and subsequent acute hypoxic responses in both, the carotid body and pulmonary vasculature. This review compares basic mitochondrial oxygen sensing mechanisms in the pulmonary vasculature and the carotid body.
... This relationship is, in part, explained by the significant hypexemia and hypercapnia [27] associated with SAS. SAS-induced chronic intermittent hypoxia stimulates the secretion of inflammatory cytokines like IL-6, TNFα, and CPR [28], and it causes pulmonary hypertension [29]. Prolonged mechanical ventilation and worsening of lungs can increase chances of pneumonia, which, in turn, elongates hospitalization time. ...
Background
Patients suffering from aortic dissection (AD) often experience sleep apnea syndrome (SAS), which aggravates their respiratory function and aortic false lumen expansion.
Methods
We analyzed the peri-operative data of Stanford A AD patients, with or without SAS, between January 2017 and June 2019. Subjects were separated into SAS positive (SAS ⁺ ) and SAS negative (SAS ⁻ ) cohorts, based on the Apnea-Hypopnea Index (AHI) and the Oxygen Desaturation Index (ODI). We next analyzed variables between the SAS ⁺ and SAS ⁻ groups.
Results
155, out of 198 AAD patients, were enlisted for this study. SAS ⁺ patients exhibited higher rates of pneumonia ( p < 0.001), heart failure (HF, p = 0.038), acute kidney injury (AKI, p = 0.001), ventilation time ( p = 0.009), and hospitalization duration ( p < 0.001). According to subsequent follow-ups, the unstented aorta false lumen dilatation (FLD) rate increased markedly, with increasing degree of SAS ( p < 0.001, according to AHI and ODI). The SAS ⁺ patients exhibited worse cumulative survival rate ( p = 0.025). The significant risk factors (RF) for poor survival were: severe ( p = 0.002) or moderate SAS ( p = 0.008), prolonged ventilation time ( p = 0.018), AKI ( p = 0.015), HF New York Heart Association (NYHA) IV ( p = 0.005) or III ( p = 0.015), pneumonia ( p = 0.005), Marfan syndrome ( p = 0.010), systolic blood pressure (BP) upon arrival ( p = 0.009), and BMI ≥ 30 ( p = 0.004).
Conclusions
SAS ⁺ Stanford A AD patients primarily exhibited higher rates of complications and low survival rates in the mid-time follow-up. Hence, the RFs associated with poor survival must be monitored carefully in SAS patients. Moreover, the FLD rate is related to the degree of SAS, thus treating SAS may mitigate FLD.
... One of the principal effects of hypobaric hypoxia exposure is hypoxic pulmonary artery vasoconstriction (HPV), which leads to the redistribution of blood to lung areas with the greatest ventilation [69]. Notably, when HPV is exacerbated and/or permanent, the pulmonary artery activates the vascular remodeling process, which increases vascular resistance and pulmonary artery pressure, leading to pulmonary hypertension-specifically HAPH [70][71][72]. ...
Several diseases associated with high-altitude exposure affect unacclimated individuals. These diseases include acute mountain sickness (AMS), high-altitude cerebral edema (HACE), high-altitude pulmonary edema (HAPE), chronic mountain sickness (CMS), and, notably, high-altitude pulmonary hypertension (HAPH), which can eventually lead to right ventricle hypertrophy and heart failure. The development of these pathologies involves different molecules and molecular pathways that might be related to oxidative stress. Studies have shown that acute, intermittent, and chronic exposure to hypobaric hypoxia induce oxidative stress, causing alterations to molecular pathways and cellular components (lipids, proteins, and DNA). Therefore, the aim of this review is to discuss the oxidative molecules and pathways involved in the development of high-altitude diseases. In summary, all high-altitude pathologies are related to oxidative stress, as indicated by increases in the malondialdehyde (MDA) biomarker and decreases in superoxide dismutase (SOD) and glutathione peroxidase (GPx) antioxidant activity. In addition, in CMS, the levels of 8-iso-PGF2α and H2O2 are increased, and evidence strongly indicates an increase in Nox4 activity in HAPH. Therefore, antioxidant treatments seem to be a promising approach to mitigating high-altitude pathologies.
... The increase in resistance of pulmonary arterioles, produced by the hypoxia-induced rise in arterial smooth muscle cell tone, is associated with the modulation of different ion channels activity. Transient Receptor Potential (TRP) channels, L-type Ca 2+ channels, K v channels as BK, and TWIK-related tandem pore domain acid-sensitive K + channel (TASK)-type are important to set the resting membrane potential and modulate membrane depolarization (Wang J. et al., 2006;Weissmann et al., 2006;Sommer et al., 2008;Whitman et al., 2008;Jonz et al., 2016). In the next sections, we will describe the direct effect of hypoxia on the activity of the large conductance, Ca 2+ -activated K + (BK), and their association with pathological conditions underpinning cardiovascular diseases. ...
Hypoxia is a condition characterized by a reduction of cellular oxygen levels derived from alterations in oxygen balance. Hypoxic events trigger changes in cell-signaling cascades, oxidative stress, activation of pro-inflammatory molecules, and growth factors, influencing the activity of various ion channel families and leading to diverse cardiovascular diseases such as myocardial infarction, ischemic stroke, and hypertension. The large-conductance, calcium and voltage-activated potassium channel (BK) has a central role in the mechanism of oxygen (O2) sensing and its activity has been related to the hypoxic response. BK channels are ubiquitously expressed, and they are composed by the pore-forming α subunit and the regulatory subunits β (β1–β4), γ (γ1–γ4), and LINGO1. The modification of biophysical properties of BK channels by β subunits underly a myriad of physiological function of these proteins. Hypoxia induces tissue-specific modifications of BK channel α and β subunits expression. Moreover, hypoxia modifies channel activation kinetics and voltage and/or calcium dependence. The reported effects on the BK channel properties are associated with events such as the increase of reactive oxygen species (ROS) production, increases of intracellular Calcium ([Ca²⁺]i), the regulation by Hypoxia-inducible factor 1α (HIF-1α), and the interaction with hemeproteins. Bronchial asthma, chronic obstructive pulmonary diseases (COPD), and obstructive sleep apnea (OSA), among others, can provoke hypoxia. Untreated OSA patients showed a decrease in BK-β1 subunit mRNA levels and high arterial tension. Treatment with continuous positive airway pressure (CPAP) upregulated β1 subunit mRNA level, decreased arterial pressures, and improved endothelial function coupled with a reduction in morbidity and mortality associated with OSA. These reports suggest that the BK channel has a role in the response involved in hypoxia-associated hypertension derived from OSA. Thus, this review aims to describe the mechanisms involved in the BK channel activation after a hypoxic stimulus and their relationship with disorders like OSA. A deep understanding of the molecular mechanism involved in hypoxic response may help in the therapeutic approaches to treat the pathological processes associated with diseases involving cellular hypoxia.
... Parmi les paramètres responsables de l'hyperréactivité artérielle, on note que les flux calciques sont augmentés. En effet, l'hypoxie présente dans l'HTP peut induire diminution d'expression des canaux potassiques, ce qui provoque une dépolarisation des cellules musculaires lisses de l'artère pulmonaire (CMLAP) et la libération de calcium intracellulaire, augmentant la capacité de contraction des cellules (Sommer et al. 2008;Yuan and al. 1998). D'ailleurs, des mutations des canaux calciques sont décrites dans les formes familiales de l'HTP, ce qui indique que le dysfonctionnement peut aussi avoir d'une origine génétique (Ma and al. 2013). ...
L’hypertension artérielle pulmonaire (HTAP) et la bronchopneumopathie chronique obstructive (BPCO) sont deux pathologies pulmonaires graves dans lesquelles les productions accrues de cytokines pro-inflammatoires et de chimiokines contribuent au développement de l’inflammation au niveau pulmonaire et à la progression de la maladie. Ne disposant à ce jour d’aucun traitement curatif, il est essentiel de chercher à mieux comprendre les mécanismes de ces pathologies dans l’espoir d’identifier de potentielles nouvelles cibles thérapeutiques. Dans ces travaux, nous avons pu confirmer l’implication de la voie de signalisation JAK/STAT dans la réponse inflammatoire et chimiotactique des macrophages humains exposés à de la fumée de cigarette et du LPS. De plus, l’utilisation d’inhibiteurs de cette voie a permis de modérer cette réponse inflammatoire sans excessivement affaiblir la capacité des macrophages à lutter contre les pathogènes, en faisant une cible thérapeutique prometteuse dans le traitement de la BPCO. Nous avons aussi pu évaluer les effets du facteur de croissance des nerfs (NGF) sur les monocytes humains non différenciés, ce qui nous a dans un premier temps amenés à soulever une problématique méthodologique concernant l’usage de l’albumine bovine comme protéine de transport pour le NGF, de par sa capacité à induire des réponses variées dans nos cellules. Nous avons ensuite pu mettre en évidence une potentielle capacité du NGF, s’il est associé à d’autres stimulus, à induire la production de cytokines pro-inflammatoires et de chimiokines par les monocytes humains non différenciés. Ces résultats soutiennent l’idée que le blocage de l’action du NGF puisse être bénéfique dans le traitement contre l’HTAP.
... Angptl4 plays a variety of roles, but its most important role is the regulation of angiogenesis, lipid metabolism, and carbohydrate metabolism. Angiogenesis is not only a normal physiological process of growth and development in the body but is also an important pathological basis of the development of tumours and cardiovascular disease, and for the elicitation of various inflammatory reactions (Murohara et al., 1998;Cazes et al., 2006;Zhang et al., 2003;Galaup et al., 2006;Sommer et al., 2008). Angptl4 levels were increased in both human alveolar epithelial A549 cells and lung tissues obtained from a mouse model of lipopolysaccharide-induced, acute lung injury (LPS-induced ALI). ...
The plateau pika, a typical hypoxia-tolerant mammal lives 3000–5000 m above sea level on the Qinghai-Tibet Plateau, has acquired many physiological and morphological characteristics and strategies in its adaptation to sustained, high-altitude hypoxia. Blunted hypoxic pulmonary vasoconstriction is one such strategy, but the genes involved in this strategy have not been elucidated. Here, we investigated the genes involved and their expression profiles in the lung transcriptome of plateau pikas subjected to different hypoxic conditions (using low-pressure oxygen cabins). A slight, right ventricular hypertrophy was observed in pikas of the control group (altitude: 3200 m) vs. those exposed to 5000 m altitude conditions for one week. Our assembly identified 67,774 genes; compared with their expression in the control animals, 866 and 8364 genes were co-upregulated and co-downregulated, respectively, in pikas subjected to 5000 m altitude conditions for 1 and 4 w. We elucidated pathways that were associated with pulmonary vascular arterial pressure, including vascular smooth muscle contraction, HIF-1 signalling, calcium signalling, cGMP-PKG signalling, and PI3K-Akt signalling based on the differentially expressed genes; the top-100 pathway enrichments were found between the control group and the group exposed to 5000 m altitude conditions for 4 w. The mRNA levels of 18 candidate gene showed that more than 83% of genes were expressed and the number of transcriptome The up-regulated genes were EPAS1, Hbα, iNOS, CX40, CD31, PPM1B, HIF-1α, MYLK, Pcdh12, Surfactant protein B, the down-regulated genes were RYR2, vWF, RASA1, CLASRP, HIF-3α. Our transcriptome data are a valuable resource for future genomic studies on plateau pika.
