Vasoconstriction Of Pulmonary Arteries Research Articles

Comparison of CT-Determined Pulmonary Artery Diameter among Smokers and Non-smokers: A Cross-sectional Study

Introduction: Tobacco smoking is a common addiction in our society. The toxic chemical compounds present in tobacco smoke cause epithelial damage and inflammation of the airways. Chronic smoking results in the thickening of the pulmonary arterial wall and vasoconstriction, leading to the development of pulmonary arterial hypertension. Hence, measurement of pulmonary artery diameter using Contrast Enhanced Computed Tomography (CECT) may be helpful in the early detection of pulmonary arterial hypertension. Aim: To compare the diameters of the Main Pulmonary Artery (MPA), Right Pulmonary Artery (RPA), and Left Pulmonary Artery (LPA) using CECT thorax in smokers and non-smokers. Materials and Methods: A cross-sectional study was conducted from April 2021 to March 2022 in the department of radiodiagnosis, KS Hegde Hospital, Karnataka, India, consisting of 100 patients referred for CECT thorax in the age group of 18-85 years. They were divided into two groups: smokers and non-smokers, with 50 patients in each group. They were further categorised into three age groups: < 50 years, 50-60 years, and >60 years. The widest diameters of the MPA were measured at the level of bifurcation of the artery and perpendicular to the long axis of the artery. At this level, RPA and LPA diameters were measured at the widest portion on 1.25 mm axial images of the arterial phase. Variation in the pulmonary artery diameter was compared between smokers and non-smokers with respect to age and analysed by unpaired t-test and Pearson correlation. Results: Diameters of MPA, RPA, and LPA were statistically significant (p<0.05) in smokers compared to non-smokers. In smokers, MPA and RPA diameters correlated with age, which was statistically significant (p<0.05). No significant correlation (p>0.05) was shown between age and MPA, RPA, and LPA diameter in non-smokers. The mean MPA diameter showed a significant difference (p<0.05) in all three age groups. Conclusion: The diameter of the pulmonary artery is statistically significant in smokers compared to non-smokers. Hence, assessment of pulmonary artery diameters among smokers using CECT thorax will help to diagnose Pulmonary Hypertension (PH) at an early stage.

Abstract 17430: Targeting DNA Hypermethylation With Hypomethylating Drugs: Implications for Pulmonary Arterial Hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by sustained vasoconstriction and remodeling of pulmonary arteries. Excessive proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs) contribute to pulmonary artery remodeling, with limited efficacy of current pharmacotherapies. Increased DNA methylation (DNAm) has been implicated in pro-proliferative phenotypes and disease progression in cancer and cardiovascular diseases. Hypothesis: We hypothesized that increased DNAm contributes to the pro-survival phenotype of PAH-PASMCs and that targeting DNA methylation could improve PAH development. Methods and Results: Our study revealed a global increase of DNAm in remodeled pulmonary arteries of human PAH patients and three preclinical models (namely monocrotaline, sugen hypoxia, Fawn hooded rats, p<0.05, immunofluorescence [IF] 5mc/SMA). In vitro, PAH-PASMCs exhibited elevated DNAm levels (IF 5mc, p<0.05), increased expression of DNA methyltransferases (DNMT1, DNMT3a; Western blot [WB], p<0.05), and decreased expression of DNA demethylase (TET2; WB, p<0.05). Consequently, hypomethylating drug Zebularine demonstrated dose-dependent reductions in PAH-PASMC proliferation (WB for surviving, plk1, MCM2; IF ki67, p<0.05) and increased apoptosis (WB for Bax/BCL2; IF annexinV, p<0.05,). Transcriptomic and gene ontology analyses indicated that these effects likely involve the downregulation of biological processes related to the cell cycle and mitosis. In vivo treatment with Zebularine (10 mg/kg, 2 weeks, intraperitoneal injection) improved PAH hemodynamics (e.g., decreased RVSP, vascular resistances, p<0.05), decreased PASMC methylation (IF 5mc/SMA, p<0.05) and proliferation (IF ki67/SMA, p<0.05), and mitigated adverse pulmonary vascular remodeling in two rodent models of the disease (monocrotaline and sugen hypoxia). Statistics: unpaired t test (2 groups), ANOVA (> 2 groups). Conclusions: Our findings demonstrate an association between increased DNA methylation and PAH development. Targeting DNAm represents a potential therapeutic avenue for PAH, as evidenced by the beneficial effects of Zebularine in improving PAH-related phenotypes.

Pulmonary hypertension: calcium channel-mediated signaling, present and future pharmacological targets

Pulmonary arterial hypertension is characterized by increased mean pulmonary arterial pressure, resistance, and pathological remodeling of pulmonary arteries. Calcium entry from the extracellular to the intracellular space through voltage-dependent and -independent channels play a major role in the increase of contractility of pulmonary arteries and in the loss of regulation of the proliferative behavior of the cells from the different layers of the pulmonary arterial wall. In doing so, these channels contribute to enhanced vasoconstriction of pulmonary arteries and their pathological remodeling. This review aims to summarize the evidence obtained from animal and cellular models regarding the involvement of the main plasma membrane calcium channels in these key pathophysiological processes for pulmonary arterial hypertension, discussing the potential value as pharmacological targets for therapies in the present and the future.

Oxidative Stress and Antioxidant Therapy in Pulmonary Hypertension.

Pulmonary hypertension (PH) is a progressive disease characterized by elevated artery pressures and pulmonary vascular resistance. Underlying mechanisms comprise endothelial dysfunction, pulmonary artery remodeling and vasoconstriction. Several studies have shown evidence of the critical role of oxidative stress in PH pathophysiology. Alteration of redox homeostasis produces excessive generation of reactive oxygen species, inducing oxidative stress and the subsequent alteration of biological molecules. Exacerbations in oxidative stress production can lead to alterations in nitric oxide signaling pathways, contributing to the proliferation of pulmonary arterial endothelial cells and smooth muscle cells, inducing PH development. Recently, antioxidant therapy has been suggested as a novel therapeutic strategy for PH pathology. However, the favorable outcomes observed in preclinical studies have not been consistently reproduced in clinical practice. Therefore, targeting oxidative stress as a therapeutic intervention for PH is an area that is still being explored. This review summarizes the contribution of oxidative stress to the pathogenesis of the different types of PH and suggests antioxidant therapy as a promising strategy for PH treatment.

Sigma-1 receptor modulation fine-tunes KV1.5 channels and impacts pulmonary vascular function

KV1.5 channels are key players in the regulation of vascular tone and atrial excitability and their impairment is associated with cardiovascular diseases including pulmonary arterial hypertension (PAH) and atrial fibrillation (AF). Unfortunately, pharmacological strategies to improve KV1.5 channel function are missing. Herein, we aimed to study whether the chaperone sigma-1 receptor (S1R) is able to regulate these channels and represent a new strategy to enhance their function. By using different electrophysiological and molecular techniques in X. laevis oocytes and HEK293 cells, we demonstrate that S1R physically interacts with KV1.5 channels and regulate their expression and function. S1R induced a bimodal regulation of KV1.5 channel expression/activity, increasing it at low concentrations and decreasing it at high concentrations. Of note, S1R agonists (PRE084 and SKF10047) increased, whereas the S1R antagonist BD1047 decreased, KV1.5 expression and activity. Moreover, PRE084 markedly increased KV1.5 currents in pulmonary artery smooth muscle cells and attenuated vasoconstriction and proliferation in pulmonary arteries. We also show that both KV1.5 channels and S1R, at mRNA and protein levels, are clearly downregulated in samples from PAH and AF patients. Moreover, the expression of both genes showed a positive correlation. Finally, the ability of PRE084 to increase KV1.5 function was preserved under sustained hypoxic conditions, as an in vitro PAH model. Our study provides insight into the key role of S1R in modulating the expression and activity of KV1.5 channels and highlights the potential role of this chaperone as a novel pharmacological target for pathological conditions associated with KV1.5 channel dysfunction.

Cigarette smoke induces pulmonary arterial dysfunction through an imbalance in the redox status of the soluble guanylyl cyclase.

Chronic obstructive pulmonary disease (COPD), whose main risk factor is cigarette smoking (CS), is one of the most common diseases globally. Some COPD patients also develop pulmonary hypertension (PH), a severe complication that leads to premature death. Evidence suggests reactive oxygen species (ROS) involvement in COPD and PH, especially regarding pulmonary artery smooth muscle cells (PASMC) dysfunction. However, the effects of CS-driven oxidative stress on the pulmonary vasculature are not completely understood. Herein we provide evidence on the effects of CS extract (CSE) exposure on PASMC regarding ROS production, antioxidant response and its consequences on vascular tone dysregulation. Our results indicate that CSE exposure promotes mitochondrial fission, mitochondrial membrane depolarization and increased mitochondrial superoxide levels. However, this superoxide increase did not parallel a counterbalancing antioxidant response in human pulmonary artery (PA) cells. Interestingly, the mitochondrial superoxide scavenger mitoTEMPO reduced mitochondrial fission and membrane potential depolarization caused by CSE. As we have previously shown, CSE reduces PA vasoconstriction and vasodilation. In this respect, mitoTEMPO prevented the impaired nitric oxide-mediated vasodilation, while vasoconstriction remained reduced. Finally, we observed a CSE-driven downregulation of the Cyb5R3 enzyme, which prevents soluble guanylyl cyclase oxidation in PASMC. This might explain the CSE-mediated decrease in PA vasodilation. These results provide evidence that there might be a connection between mitochondrial ROS and altered vasodilation responses in PH secondary to COPD, and strongly support the potential of antioxidant strategies specifically targeting mitochondria as a new therapy for these diseases.

Piezo1 Channel Activation Reverses Pulmonary Artery Vasoconstriction in an Early Rat Model of Pulmonary Hypertension: The Role of Ca2+ Influx and Akt-eNOS Pathway.

In intrapulmonary arteries (IPAs), mechanical forces due to blood flow control vessel tone, and these forces change during pulmonary hypertension (PH). Piezo1, a stretch-activated calcium channel, is a sensor of mechanical stress present in both endothelial cells (ECs) and smooth muscle cells (SMCs). The present study investigated the role of Piezo1 on IPA in the chronic hypoxia model of PH. Rats were raised in chronically hypoxic conditions for 1 (1W-CH, early stage) or 3 weeks (3W-CH, late-stage) of PH or in normoxic conditions (Nx). Immunofluorescence labeling and patch-clamping revealed the presence of Piezo1 in both ECs and SMCs. The Piezo1 agonist, Yoda1, induced an IPA contraction in Nx and 3W-CH. Conversely, Yoda1 induced an endothelial nitric oxide (eNOS) dependent relaxation in 1W-CH. In ECs, the Yoda1-mediated intracellular calcium concentration ([Ca2+]i) increase was greater in 1W-CH as compared to Nx. Yoda1 induced an EC hyperpolarization in 1W-CH. The eNOS levels were increased in 1W-CH IPA compared to Nx or 3W-CH PH and Yoda1 activated phosphorylation of Akt (Ser473) and eNOS (Ser1177). Thus, we demonstrated that endothelial Piezo1 contributes to intrapulmonary vascular relaxation by controlling endothelial [Ca2+]i, endothelial-dependent hyperpolarization, and Akt-eNOS pathway activation in the early stage of PH.

Artemisinin and Its Derivate Alleviate Pulmonary Hypertension and Vasoconstriction in Rodent Models.

Background Pulmonary arterial hypertension (PAH) is a complex pulmonary vasculature disease characterized by progressive obliteration of small pulmonary arteries and persistent increase in pulmonary vascular resistance, resulting in right heart failure and death if left untreated. Artemisinin (ARS) and its derivatives, which are common antimalarial drugs, have been found to possess a broad range of biological effects. Here, we sought to determine the therapeutic benefit and mechanism of ARS and its derivatives treatment in experimental pulmonary hypertension (PH) models. Methods Isolated perfused/ventilated lung and isometric tension measurements in arteries were performed to test pulmonary vasoconstriction and relaxation. Monocrotaline (MCT) and hypoxia+Su5416 (SuHx) were administered to rats to induce severe PH. Evaluation methods of ARS treatment and its derivatives in animal models include echocardiography, hemodynamics measurement, and histological staining. In vitro, the effect of these drugs on proliferation, viability, and hypoxia-inducible factor 1α (HIF1α) was examined in human pulmonary arterial smooth muscle cells (hPASMCs). Results ARS treatment attenuated pulmonary vasoconstriction induced by high K+ solution or alveolar hypoxia, decreased pulmonary artery (PA) basal vascular tension, improved acetylcholine- (ACh-) induced endothelial-dependent relaxation, increased endothelial nitric oxide (NO) synthase (eNOS) activity and NO levels, and decreased levels of NAD(P)H oxidase subunits (NOX2 and NOX4) expression, NAD(P)H oxidase activity, and reactive oxygen species (ROS) levels of pulmonary arteries (PAs) in MCT-PH rats. NOS inhibitor, L-NAME, abrogated the effects of ARS on PA constriction and relaxation. Furthermore, chronic application of both ARS and its derivative dihydroartemisinin (DHA) attenuated right ventricular systolic pressure (RVSP), Fulton index (right ventricular hypertrophy), and vascular remodeling of PAs in the two rat PH models. In addition, DHA inhibited proliferation and migration of hypoxia-induced PASMCs. Conclusions In conclusion, these results indicate that treatment with ARS or DHA can inhibit PA vasoconstriction, PASMC proliferation and migration, and vascular remodeling, as well as improve PA endothelium-dependent relaxation, and eventually attenuate the development and progression of PH. These effects might be achieved by decreasing NAD(P)H oxidase generated ROS production and increasing eNOS activation to release NO in PAs. ARS and its derivatives might have the potential to be novel drugs for the treatment of PH.

Targeting Piezo1 channels to reverse pulmonary artery vasoconstriction in rat model of pulmonary hypertension

Piezo1, a stretch-activated calcium permeable channel is a sensor of mechanical stress present in endothelial cells (ECs) and vascular smooth muscle cells (SMCs). Our previous studies have shown that endothelial Piezo1 contributes to intrapulmonary artery (IPA) relaxation in mice. The present study was undertaken to investigate the implication of Piezo1 in both rat ECs and SMCs in pulmonary hypertension (PH). Chronically hypoxic rats, an animal model of PH, were exposed to chronic hypoxia (CH, −50% O 2 for 1 week), whereas normoxic rats were housed in normoxic condition (NX). NX or CH IPA tone variation induced by YODA1 was quantified by myograph. Intracellular calcium concentration ([Ca2+]i) was determined with Cal520-AM probes. Protein levels of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (peNOS), Akt and pAkt were quantified by Western blot analysis. Immunofluorescence labeling and patch-clamp revealed the presence of Piezo1 in both ECs and SMCs. In IPAs, YODA1 induced a contraction in NX condition. By contrast, YODA1 induced an endothelium and nitric oxide-dependent relaxation in CH IPAs. Activation of Piezo1 channels by its agonist YODA1 increased [Ca2+]i. However, the [Ca2+]i increase in ECs was greater in CH as compared to NX condition. In addition, CH condition increased level of eNOS proteins as compared to NX condition and YODA1 induced a phosphorylation of Akt (Ser 473) and eNOS (Ser 1177) in NX and CH conditions. The present study thus demonstrates that endothelial Piezo1 contributes to intrapulmonary vascular relaxation by controlling endothelial [Ca2+]i and Akt-eNOS- pathway activation that could counteract PH.

High magnesium mitigates the vasoconstriction mediated by different types of calcium influx from monocrotaline-induced pulmonary hypertensive rats.

What is the central question of this study? What is the involvement of Mg2+ in mitigating the vasoconstriction in pulmonary arteries and smaller pulmonary arteries in the monocrotaline-induced pulmonary arterial hypertension (MCT-PAH) rat model? What are the main finding and its importance? Both store-operated Ca2+ entry- and receptor-operated Ca2+ entry-mediated vasoconstriction were enhanced in the MCT-PAH model. High magnesium inhibited vasoconstriction by directly antagonizing Ca2+ and increasing NO release, and this was more notable in smaller pulmonary arteries. Increased extracellular magnesium concentration has been shown to attenuate the endothelin-1-induced contractile response via the release of nitric oxide (NO) from the endothelium in proximal pulmonary arteries (PAs) of chronic hypoxic mice. Here, we further examined the involvement of Mg2+ in the inhibition of vasoconstriction in PAs and distal smaller pulmonary arteries (sPAs) in a monocrotaline-induced pulmonary arterial hypertension (MCT-PAH) rat model. The data showed that in control rats vasoconstriction in sPAs is more intense than that in PAs. In MCT-PAH rats, store-operated Ca2+ entry (SOCE)- and receptor-operated Ca2+ entry (ROCE)-mediated contraction were significantly strengthened. However, there was no upregulation of the vasoconstriction mediated by voltage-dependent calcium entry (VDCE). Furthermore, high magnesium greatly inhibited VDCE-mediated contraction in PAs rather than sPAs, which was the opposite of the ROCE-mediated contraction. Moreover, monocrotaline pretreatment partly eliminated the endothelium-dependent vasodilatation in PAs, which in sPAs, however, was still promoted by magnesium due to the increased NO release in pulmonary microvascular endothelial cells (PMVECs). In conclusion, the findings suggest that both SOCE- and ROCE-mediated vasoconstriction in the MCT-PAH model are enhanced, especially in sPAs. The inhibitory effect of high magnesium on vasoconstriction can be achieved partly by its direct role as a Ca2+ antagonist and partly by increasing NO release in PMVECs.

Treating Inflammation Associated with Pulmonary Hypertension: An Overview of the Literature.

Pulmonary hypertension (PH) comprises five groups of serious clinical entities characterized by pulmonary artery vasoconstriction and vascular remodeling leading to right heart failure and death. In addition to vascular remodeling, recruitment and exaggerated accumulation of several perivascular inflammatory cells is also observed, including macrophages, monocytes, T and B-lymphocytes, dendritic cells and mast cells distributed in pulmonary perivascular spaces and around remodeling pulmonary vessels. Current pulmonary arterial hypertension (PAH)-targeted therapies aim to improve functional capacity, pulmonary hemodynamic conditions, and delay disease progression. Nevertheless, PAH remains incurable, with a poor prognosis and is often refractory to drug therapy, highlighting the need for further research. In the last three decades, the best pathophysiological understanding of PAH has allowed for progression from a disease of little-known pathogenesis, without specific and effective therapy to expanding the arsenal of drugs on a cellular, genetic and molecular basis. This article provides an overview on current knowledge and progress in recent advances in pharmacological therapy in PAH.

Targeting Piezo1 channels to reverse pulmonary artery vasoconstriction in rat model of pulmonary hypertension

Piezo1, a stretch-activated calcium permeable channel is a sensor of mechanical stress present in endothelial cells (ECs) and vascular smooth muscle cells (SMCs). Our previous studies have shown that endothelial Piezo1 contributes to intrapulmonary artery (IPA) relaxation in mice. The present study was undertaken to investigate the implication of Piezo1 in both rat ECs and SMCs in pulmonary hypertension (PH). Chronically hypoxic rats, an animal model of PH, were exposed to chronic hypoxia (CH, −50% O2 for 1 weeks), whereas normoxic rats were housed in normoxic condition (NX). NX or CH IPA tone variation induced by YODA1 was quantified by myograph. Intracellular calcium concentration ([Ca2+]i) was determined with Cal520-AM probes. Protein levels of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (peNOS), Akt and pAkt were quantified by Western blot analysis. Immunofluorescence labeling and patch-clamp revealed the presence of Piezo1 in both ECs and SMCs. In IPAs, YODA1 induced a contraction in NX condition. By contrast, YODA1 induced an endothelium and nitric oxide-dependent relaxation in CH IPAs. Activation of Piezo1 channels by its agonist YODA1 increased [Ca2+]i. However, the [Ca2+]i increase in ECs was greater in CH as compared to NX condition. In addition, CH condition increased level of eNOS proteins as compared to NX condition and YODA1 induced a phosphorylation of Akt (Ser 473) and eNOS (Ser 1177) in NX and CH conditions. The present study thus demonstrates that endothelial Piezo1 contributes to intrapulmonary vascular relaxation by controlling endothelial [Ca2+]i and Akt-eNOS- pathway activation that could counteract PH.

Acute Pulmonary Embolism and Chronic Thromboembolic Pulmonary Hypertension: Clinical and Serial CT Pulmonary Angiographic Features.

In acute pulmonary embolism (PE), circulatory failure and systemic hypotension are important clinically for predicting poor prognosis. While pulmonary artery (PA) clot loads can be an indicator of the severity of current episode of PE or treatment effectiveness, they may not be used directly as an indicator of right ventricular (RV) failure or patient death. In other words, pulmonary vascular resistance or patient prognosis may not be determined only with mechanical obstruction of PAs and their branches by intravascular clot loads on computed tomography pulmonary angiography (CTPA), but determined also with vasoactive amines, reflex PA vasoconstriction, and systemic arterial hypoxemia occurring during acute PE. Large RV diameter with RV/left ventricle (LV) ratio > 1.0 and/or the presence of occlusive clot and pulmonary infarction on initial CTPA, and clinically determined high baseline PA pressure and RV dysfunction are independent predictors of oncoming chronic thromboembolic pulmonary hypertension (CTEPH). In this pictorial review, authors aimed to demonstrate clinical and serial CTPA features in patients with acute massive and submassive PE and to disclose acute CTPA and clinical features that are related to the prediction of oncoming CTEPH.

DON'T TAKE MY BREATH AWAY: A CASE OF HIGH-RISK PULMONARY EMBOLISM IN THE SETTING OF PATENT FORAMEN OVALE REQUIRING EXTRACORPOREAL MEMBRANE OXYGENATION

TOPIC: Pulmonary Vascular Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Pulmonary emboli precipitate cardiovascular collapse by mechanical obstruction of the right ventricular outflow tract and pulmonary artery vasoconstriction, leading to right ventricular overload. The presence of a patent foramen ovale (PFO) can subvert this typical physiology by creating a right-to-left shunt, permitting left ventricular filling and near-normal cardiac output. However, this also causes intracardiac mixing of oxygenated and deoxygenated blood, which can further worsen hypoxemia. Here, we present a patient with saddle pulmonary emboli who was incidentally found to have a PFO due to persistent hypoxemia. CASE PRESENTATION: A 67-year-old man with a past medical history of coronary artery disease, alcohol abuse, hypertension, hyperlipidemia, and obstructive sleep apnea presented with word-finding difficulty and behavioral changes. He was found to have acute occlusion of the bilateral middle cerebral arteries, requiring mechanical thrombectomy. He was recovering successfully when he suddenly developed dyspnea and lightheadedness with exertion, which rapidly progressed to mechanical ventilation. He remained hypoxic on optimal ventilator settings and inhaled nitric oxide, prompting suspicion for acute pulmonary embolism. Chest x-ray was unchanged. EKG showed inferior ST-segment elevations, and a trans-thoracic echocardiogram revealed a newly dilated and overloaded right ventricle with an underfilled left ventricle, as well as McConnell's sign. Transesophageal echocardiogram showed a saddle pulmonary embolus and an incidental PFO with right-to-left shunting. Veno-venous extracorporeal membrane oxygenation (ECMO) was initiated as a bridge to mechanical thrombectomy. His course was complicated by cardiogenic shock, septic shock, and progression of his initial ischemic stroke. Encephalopathy remained a barrier to extubation. DISCUSSION: Recent studies have recognized ECMO as a promising adjunctive therapy for pulmonary emboli for those who are too unstable for surgical thrombectomy or who have contraindications to systemic thrombolysis. Our patient was not a candidate for thrombolysis given his recent stroke. His PFO, while beneficial in preventing florid cardiogenic shock by offloading the right ventricle, caused hypoxemia refractory to mechanical ventilation alone. As such, ECMO was a crucial temporizing measure until the patient was stable enough for surgical thrombectomy. CONCLUSIONS: This case highlights, prompt recognition of intracardiac shunts in cases of refractory hypoxemia, and the importance of early identification of patients who need advanced intervention such as ECMO. REFERENCE #1: Al-Bawardy R, Rosenfield K, Borges J, Young MN, Albaghdadi M, Rosovsky R, Kabrhel C. Extracorporeal membrane oxygenation in acute massive pulmonary embolism: a case series and review of the literature. Perfusion. 2019 Jan;34(1):22-28. doi: 10.1177/0267659118786830. Epub 2018 Jul 16. PMID: 30009670. REFERENCE #2: Askari K, Sneij W, Krick S, Alvarez RA. Going with the Flow: Saddle Pulmonary Embolism Complicated by Severe Hypoxemia without Shock. Annals of the American Thoracic Society. 2017;14(9):1479-1484. doi:10.1513/annalsats.201702-145cc REFERENCE #3: Corsi F, Lebreton G, Bréchot N, Hekimian G, Nieszkowska A, Trouillet JL, Luyt CE, Leprince P, Chastre J, Combes A, Schmidt M. Life-threatening massive pulmonary embolism rescued by venoarterial-extracorporeal membrane oxygenation. Crit Care. 2017 Mar 28;21(1):76. doi: 10.1186/s13054-017-1655-8. PMID: 28347320; PMCID: PMC5369216 DISCLOSURES: No relevant relationships by Sonali Bishnoi, source=Web Response No relevant relationships by Scott Blumhof, source=Web Response No relevant relationships by Amy Lam, source=Web Response No relevant relationships by Kaitlyn Musco, source=Web Response No relevant relationships by Jeffrey Wright, source=Web Response

Acid-sensing ion channel 1 contributes to pulmonary arterial smooth muscle cell depolarization following hypoxic pulmonary hypertension.

Pulmonary hypertension is characterized by sustained vasoconstriction and remodelling of the small pulmonary arteries, which is associated with persistent depolarization of the resting membrane potential (Em ) of pulmonary arterial smooth muscle cells (PASMCs). It is well-known that the underlying mechanism of this depolarization includes inhibition of K+ channels; however, whether other ion channels contribute to this depolarization is unknown. We previously reported that acid-sensing ion channel 1 (ASIC1), a non-selective cation channel (NSCC) that conducts both Na+ and Ca2+ , is present in PASMCs and contributes to the development of chronic hypoxia (CH)-induced pulmonary hypertension. Therefore, we tested the hypothesis that ASIC1-mediated Na+ influx contributes to PASMC Em regulation following CH-induced pulmonary hypertension. Using sharp electrode intracellular recordings in isolated, pressurized small pulmonary arteries from rats and mice, we show that exposure to CH leads to PASMC membrane depolarization compared with control animals, and this is independent of intraluminal pressure-induced depolarization. In addition to a decrease in PASMC whole-cell K+ currents following CH, we demonstrate that whole-cell NSCC currents are increased and essential to the persistent CH-induced Em depolarization in PASMCs. Both the specific inhibitor of ASIC1, psalmotoxin 1, and global knockout of ASIC1 (Asic1-/- ) prevents CH-induced Em depolarization and largely inhibits whole-cell NSCC currents, without affecting whole-cell K+ currents. Our results show a combination of factors, including inhibition of K+ efflux and augmented Na+ influx, mediate CH-induced PASMC depolarization. Furthermore, this study demonstrates a novel role for ASIC1 in the regulation of Em in PASMCs during CH-induced pulmonary hypertension. KEY POINTS: In pulmonary hypertensive patients and animal models of pulmonary hypertension, the resting membrane potential (Em ) of pulmonary arterial smooth muscle cells (PASMCs) is persistently depolarized. In addition to the well-established reduction of K+ conductance, we show that non-selective cation channel currents are increased and essential to the persistent Em depolarization in PASMCs following chronic hypoxia (CH)-induced pulmonary hypertension. The current study provides novel evidence that acid-sensing ion channel 1 (ASIC1)-mediated Na+ influx induces membrane depolarization and regulates Em in PASMCs following CH exposure. Although fairly quiescent under control conditions, our findings demonstrate a pathological function of ASIC1 in the development of chronic hypoxia-induced pulmonary hypertension.

Prenatal hypoxia induced ETBR activation and abnormal ROS signalling in pulmonary artery cells of rat offspring

Pulmonary arterial hypertension is a progressive disorder characterized by remodeling and increased small pulmonary arteries resistance. Endothelin-1 (ET-1) was related to PAH and ET-1 receptors were up-regulated selectively in the lung when exposed to toxic factor hypoxia. However, the role of ET-1 signaling in the pathogenesis of prenatal hypoxia-induced pulmonary abnormalities remains to be elucidated. Pregnant rats were divided into prenatal hypoxia (10.5 % O2 from gestational day 4–21) and control group. Their three-month-old offspring male rats were tested for vascular functions and molecular analysis, DNA methylation was assessed for cellular hypoxia. Functional testing showed that ET-1-mediated vasoconstriction was enhanced, and the expressions of endothelin A receptor/B receptor (ETAR/ETBR), inositol 1,4,5-trisphosphate receptor, type 1, and the sensitivity of calcium channels were increased in the small pulmonary arteries following prenatal hypoxia. q-PCR and DHE staining showed that the expressions of NADPH oxidase 1/4 (Nox1/4) were up-regulated, along with the increased production of superoxide anion. Furthermore, superoxide anion promoted ET-1-mediated pulmonary artery contraction. In the pulmonary artery smooth muscle cell experiments, q-PCR, Western Blot, CCK8 and DHE staining showed that the expressions of ETBR, Nox1/4, and superoxide anion were increased by hypoxia, along with promoted cell proliferation. 2,2,6,6-Tetramethyl-1-piperidinyloxy reversed hypoxia-induced cell proliferation. ETBR antagonist BQ788 inhibited hypoxia-increased expressions of Nox1/4, superoxide anion production, and proliferation of cells. Moreover, methylation analysis indicated that hypoxia decreased the methylation levels of the ETBR promoter in the pulmonary artery smooth muscle cells. The results indicated that prenatal toxic factor hypoxia resulted in abnormal ETBR activation, which enhanced ET-1-mediated vasoconstriction of pulmonary arteries and pulmonary artery smooth muscle cell proliferation through ETBR/Nox1/4-derived ROS pathway.

Novel Experimental Therapies for Treatment of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive and devastating disease characterized by pulmonary artery vasoconstriction and vascular remodeling leading to vascular rarefaction with elevation of pulmonary arterial pressures and pulmonary vascular resistance. Often PAH will cause death from right heart failure. Current PAH-targeted therapies improve functional capacity, pulmonary hemodynamics and reduce hospitalization. Nevertheless, today PAH still remains incurable and is often refractory to medical therapy, underscoring the need for further research. Over the last three decades, PAH has evolved from a disease of unknown pathogenesis devoid of effective therapy to a condition whose cellular, genetic and molecular underpinnings are unfolding. This article provides an update on current knowledge and summarizes the progression in recent advances in pharmacological therapy in PAH.

Cystamine Treatment Fails to Prevent the Development of Pulmonary Hypertension in Chronic Hypoxic Rats

Introduction: Pulmonary hypertension is characterized by vasoconstriction and remodeling of pulmonary arteries, leading to right ventricular hypertrophy and failure. We have previously found upregulation of transglutaminase 2 (TG2) in the right ventricle of chronic hypoxic rats. The hypothesis of the present study was that treatment with the transglutaminase inhibitor, cystamine, would inhibit the development of pulmonary arterial remodeling, pulmonary hypertension, and right ventricular hypertrophy. Methods: Effect of cystamine on transamidase activity was investigated in tissue homogenates. Wistar rats were exposed to chronic hypoxia and treated with vehicle, cystamine (40 mg/kg/day in mini-osmotic pumps), sildenafil (25 mg/kg/day), or the combination for 2 weeks. Results: Cystamine concentration-dependently inhibited TG2 transamidase activity in liver and lung homogenates. In contrast to cystamine, sildenafil reduced right ventricular systolic pressure and hypertrophy and decreased pulmonary vascular resistance and muscularization in chronic hypoxic rats. Fibrosis in the lung tissue decreased in chronic hypoxic rats treated with cystamine. TG2 expression was similar in the right ventricle and lung tissue of drug and vehicle-treated hypoxic rats. Discussion/Conclusions: Cystamine inhibited TG2 transamidase activity, but cystamine failed to prevent pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial muscularization in the chronic hypoxic rat.

Obstructive Sleep Apnea and Pulmonary Hypertension: A Review of Literature.

Obstructive sleep apnea (OSA) is a disease process involving recurrent pharyngeal collapse during sleep, resulting in apneic episodes. Clinically, symptoms can include snoring, sudden awakening with a choking-like sensation, excessive somnolence, non-restorative sleep, difficulty in starting or maintaining sleep, and fatigue. It results in impaired gas exchange, subsequently causing various cardiovascular, metabolic, and neurocognitive pathologies. Historically, OSA has been underdiagnosed and undertreated, especially in women.OSA is associated with WHO (World Health Organization) class III pulmonary hypertension (PH) or PH due to lung disease. PH is a concerning complication of OSA and thought to occur in roughly 20% of individuals with OSA. The pathogenesis of PH in OSA can include pulmonary artery vasoconstriction and remodeling. Patients suffering from OSA who develop PH tend to have worse cardiovascular and pulmonary changes. We present a thorough review of the literature examining the interplay between OSA and PH.

Pulmonary hypertension is attenuated and ventilation-perfusion matching is maintained during chronic hypoxia in deer mice native to high altitude.

Hypoxia at high altitude can constrain metabolism and performance and can elicit physiological adjustments that are deleterious to health and fitness. Hypoxic pulmonary hypertension is a particularly serious and maladaptive response to chronic hypoxia, which results from vasoconstriction and pathological remodeling of pulmonary arteries, and can lead to pulmonary edema and right ventricle hypertrophy. We investigated whether deer mice (Peromyscus maniculatus) native to high altitude have attenuated this maladaptive response to chronic hypoxia and whether evolved changes or hypoxia-induced plasticity in pulmonary vasculature might impact ventilation-perfusion (V-Q) matching in chronic hypoxia. Deer mouse populations from both high and low altitudes were born and raised to adulthood in captivity at sea level, and various aspects of lung function were measured before and after exposure to chronic hypoxia (12 kPa O2, simulating the O2 pressure at 4,300 m) for 6-8 wk. In lowlanders, chronic hypoxia increased right ventricle systolic pressure (RVSP) from 14 to 19 mmHg (P = 0.001), in association with thickening of smooth muscle in pulmonary arteries and right ventricle hypertrophy. Chronic hypoxia also impaired V-Q matching in lowlanders (measured at rest using SPECT-CT imaging), as reflected by increased log SD of the perfusion distribution (log SDQ) from 0.55 to 0.86 (P = 0.031). In highlanders, chronic hypoxia had attenuated effects on RVSP and no effects on smooth muscle thickness, right ventricle mass, or V-Q matching. Therefore, evolved changes in lung function help attenuate maladaptive plasticity and contribute to hypoxia tolerance in high-altitude deer mice.