Small Pulmonary Arteries Research Articles

Pulmonary Arteriovenous Pressure Gradient and Time-Averaged Mean Velocity of Small Pulmonary Arteries Can Serve as Sensitive Biomarkers in the Diagnosis of Pulmonary Arterial Hypertension: A Preclinical Study by 4D-Flow MRI.

(1) Background: Pulmonary arterial hypertension (PAH) is a serious condition that is associated with many cardiopulmonary diseases. Invasive right heart catheterization (RHC) is currently the only method for the definitive diagnosis and follow-up of PAH. In this study, we sought a non-invasive hemodynamic biomarker for the diagnosis of PAH. (2) Methods: We applied prospectively respiratory and cardiac gated 4D-flow MRI at a 9.4T preclinical scanner on three different groups of Sprague Dawley rats: baseline (n = 11), moderate PAH (n = 8), and severe PAH (n = 8). The pressure gradients as well as the velocity values were analyzed from 4D-flow data and correlated with lung histology. (3) Results: The pressure gradient between the pulmonary artery and vein on the unilateral side as well as the time-averaged mean velocity values of the small pulmonary arteries were capable of distinguishing not only between baseline and severe PAH, but also between the moderate and severe stages of the disease. (4) Conclusions: The current preclinical study suggests the pulmonary arteriovenous pressure gradient and the time-averaged mean velocity as potential biomarkers to diagnose PAH.

“Blue lips”: research progress in pulmonary vascular remodeling in hypoxic pulmonary hypertension

<p indent=0mm>Hypoxic pulmonary hypertension (HPH), characterized by increased pulmonary arterial pressure, is a complex and progressive disease with a wide spectrum of hypoxic etiologies and a challenging clinical problem with high disease prevalence. Mechanism-based treatment options for HPH are still lacking, and there is currently no cure for this devastating disease. Small pulmonary artery remodeling caused by chronic inflammation and aberrant oxidative stress under hypoxia is the typical pathological feature. This review summarizes the recent progress in pulmonary vascular remodeling research, including pathophysiological characteristics, pathophysiological pathogenesis, and treatment status and prospects, and provides ideas for the treatment of HPH.

Increased Lung Uric Acid Deteriorates Pulmonary Arterial Hypertension.

BackgroundRecent studies have demonstrated that uric acid (UA) enhances arginase activity, resulting in decreased NO in endothelial cells. However, the role of lung UA in pulmonary arterial hypertension (PAH) remains uncertain. We hypothesized that increased lung UA level contributes to the progression of PAH.Methods and ResultsIn cultured human pulmonary arterial endothelial cells, voltage‐driven urate transporter 1 (URATv1) gene expression was detected, and treatment with UA increased arginase activity. In perfused lung preparations of VEGF receptor blocker (SU5416)/hypoxia/normoxia‐induced PAH model rats, addition of UA induced a greater pressure response than that seen in the control and decreased lung cGMP level. UA‐induced pressor responses were abolished by benzbromarone, a UA transporter inhibitor, or L‐norvaline, an arginase inhibitor. In PAH model rats, induction of hyperuricemia by administering 2% oxonic acid significantly increased lung UA level and induced greater elevation of right ventricular systolic pressure with exacerbation of occlusive neointimal lesions in small pulmonary arteries, compared with nonhyperuricemic PAH rats. Administration of benzbromarone to hyperuricemic PAH rats significantly reduced lung UA levels without changing XOR (xanthine oxidoreductase) activity, and attenuated right ventricular systolic pressure increase and occlusive lesion development. Topiroxostat, a XOR inhibitor, significantly reduced lung XOR activity in PAH rats, with no effects on increase in right ventricular systolic pressure, arterial elastance, and occlusive lesions. XOR‐knockout had no effects on right ventricular systolic pressure increase and arteriolar muscularization in hypoxia‐exposed mice.ConclusionsIncreased lung UA per se deteriorated PAH, whereas XOR had little impact. The mechanism of increased lung UA may be a novel therapeutic target for PAH complicated with hyperuricemia.

Abstract 12410: The Critical Role of Mitochondrial Dysfunction in the Impaired Angiogenesis Associated With the Pulmonary Hypertensive Phenotype

Introduction: Mitochondrial dysfunction (MD) is known to be tightly associated with the pathobiology of pulmonary arterial hypertension (PAH). Recently, we discovered that rats reproducing a human mutation in NFU1 (NFU1 G206C ) have a severely altered mitochondrial function and spontaneously develop PAH characterized by increased right ventricle (RV) systolic pressure, RV hypertrophy, and severe obliterative disease of small pulmonary arteries. Hypothesis: In this study, we investigated whether MD induced by NFU1 mutation is sufficient to impair pulmonary angiogenesis contributing to PAH pathogenesis. Methods: Angiogenesis was assessed by micro-computed tomography of the pulmonary vasculature, microangiography of small pulmonary arteries (PAs), and histological evaluation of pulmonary capillary density. The angiogenic capacity was also investigated in vitro using cell migration and tube formation assays and analysis of EC tip cell population by flow cytometry. Results: MD significantly reduced the complexity of the pulmonary vascular network and prevented its further advancement (PA density (mean intensity/pxl) in WT vs. NFU1 G206C at 6 and 10 wks of age is 0.07±0.004 vs. 0.03±0.002 and 0.1±0.004 vs. 0.04±0.003; p&lt;0.0001; N=5). NFU1 G206C rats had a reduced number of PA branches and junctions and impaired PA capillary density. PA endothelial cells isolated from NFU1 G206C rats demonstrated a strongly attenuated cell migration (~30% of WT) and tube formation capacity and a ~2.2 fold decrease in the number of CD-304 positive EC tip cells. Supplementation of NFU1 G206C rats with lipoic acid (LA, 1.70 mM in drinking water) aimed to attenuate the LA-synthase insufficiency secondary to NFU1 mutation, restored mitochondrial function, preserved the complexity of PA vascular network at WT level, and averted the PAH phenotype. Conclusions: We conclude that MD plays a causative role in the impaired pulmonary angiogenesis. Indeed, the lungs of NFU1 G206C rats fully reproduced the “dead-tree” picture of pulmonary vasculature described in PAH patients. At the same time, normalized mitochondrial function was sufficient to preserve pulmonary angiogenesis and prevent the PAH, suggesting the protective role of MD ameliorative approaches.

Abstract 10294: Endothelial Pannexin1-TRPV4 Signaling Regulates Pulmonary Arterial Pressure

The pulmonary endothelial cells (EC) dilate small pulmonary arteries (PAs) and maintain low pulmonary arterial pressure (PAP). Importantly, the loss of EC function contributes to elevated PAP in pulmonary hypertension (PH). Recent studies show that Pannexin 1 (Panx1), an ATP efflux pathway at the cell membrane, is a critical regulator of endothelial function. However, the impact of endothelial Panx1 (Panx1 EC ) on PA contractility and PAP is unknown. We observed that the extracellular ATP (eATP) levels are reduced in PAs from inducible, EC-specific Panx1 -/- (Panx1 EC -/- ) mice, identifying Panx1 EC as an important ATP release pathway in PAs. Our recently published findings demonstrated that eATP dilates PAs via activation of Ca 2+ influx through endothelial transient receptor potential vanilloid 4 (TRPV4 EC ) ion channels. Therefore, we hypothesized that endothelial Panx1—eATP—TRPV4 channel signaling dilates PAs and lowers resting PAP. Apyrase (10 U/mL), an ATP hydrolyzing enzyme, reduced the activity of TRPV4 EC sparklets (individual Ca 2+ influx signals through TRPV4 EC channels) in PAs, implying a constitutive regulation of TRPV4 EC channels by ATP. The activity of TRPV4 EC sparklets was lower in PAs from Panx1 EC -/- mice than controls, identifying Panx1 EC as a novel promoter of TRPV4 EC channel activity. Pressure myography studies in PAs (~ 50 μm) from Panx1 EC -/- and TRPV4 EC -/- mice showed higher constriction to thromboxane A2 receptor agonist U46619 (1-300 nM) compared to PAs from controls. Finally, right ventricular systolic pressure was higher in Panx1 EC -/- and TRPV4 EC -/- mice compared to the respective controls. These data indicated that Panx1 EC —eATP—TRPV4 EC channel signaling lowers PA contractility and PAP. ATP is an endogenous activator of purinergic receptor signaling. Inhibition of P2Y1 and P2X receptors did not alter ATP activation of TRPV4 EC sparklets in PAs. However, P2Y2 receptor inhibition and EC-specific P2Y2 receptor deletion abolished ATP activation of TRPV4 EC sparklets. Together, these data identify a novel Panx1 EC —eATP—P2Y2R EC signaling pathway that enhances TRPV4 EC channel activity and lowers PAP. Individual elements of this pathway may provide novel therapeutic targets for treating pulmonary vascular disorders.

Long-term pathological changes in lungs after COVID-19

World literature is paying increasing attention to the long-term course of COVID-19 and symptoms that appear after the acute coronavirus infection. The symptoms, functional state of the lungs, and the X-ray changes are assessed. Nevertheless, post-COVID lung histology has not been described yet.The aim of this article is to study the long-term pathological changes in the lungs after acute COVID-19. Methods. We analyzed autopsy lung material from 19 deceased who had COVID-19. The average age of the deceased was 68.82 ± 14.6 years. All patients were found to have IgG to SARS-CoV-2. The median time to death following viral interstitial pneumonia was 72 days. Results. The causes of death and thrombotic complications (infarctions of various organs and venous thrombosis) were analyzed. Histological examination revealed thrombosis of small pulmonary arteries and capillaries of interalveolar septa, microinfarctions, hemorrhages, foci of organizing pneumonia, and nonspecific interstitial pneumonia.Conclusion. The first assessment of histological changes in human lungs showed that the most common post-COVID pathologic changes are microcirculation disorders combined with small areas of acute lung damage. The obtained data are essential for understanding the pathogenesis of post-COVID syndrome, necessitate diagnostic of microvasculature disorders using laboratory tests, scintigraphy, and CT imaging, as well as search for the therapeutic strategies.

Implications of left atrial enlargement and patent foramen ovale creation on early surgical outcomes in patients with total anomalous pulmonary venous connection.

In patients with total anomalous pulmonary venous connection (TAPVC), left atrium (LA) is small and suprasystemic pulmonary artery (PA) pressures may be present in some patients. In our study, we studied the relationship between surgical LA enlargement and patent foramen ovale (PFO) creation separately on the outcomes of patients with TAPVC. Out of the 130 patients operated in our institute between January 2014 and December 2020, LA was enlarged in 60 patients. LA enlargement was done using a larger patch for atrial septal defect (ASD) closure. Thus, the LA volume was increased by shifting the patch towards the right atrium (RA). Suprasystemic or high PA pressures were present in 60 patients. In 33 patients, PFO was created. Early surgical outcomes were determined on the basis of vasoactive inotropic score (VIS), hours of ventilation, hours of inotropic support, intensive care unit (ICU) stay, and hospital stay. Between the LA enlarged and nonenlarged group there was statistically significant less VIS score (18 [13-27.5] vs. 24 [18-30], p value .019), hours of ventilation (23 [16-46.5] vs. 26 [18-60], p value .039), hours of inotropic support (45.5 [30-72] vs. 55 [38-84], p value .038), and ICU stay (7 [5-9] vs. 8 [7-10] p value .0352) and statistically nonsignificant less hospital stay (11.5 [9-13] vs. 12 [9-14], p value .424). In patients with preoperative suprasystemic or high PA pressures, there was a statistically significant less VIS score (16 [11-23.5] vs. 18 [13-25], p value .044), hours of ventilation (20 [14-37] vs. 22 [18-39], p value .038), hours of inotropic support (34 [29.5-71] vs. 38 [30-78], p value .042), and hospital stay (9 [5-12] vs. 11 [9-14], p value .038) and statistically nonsignificant less ICU stay (7 [5.5-9] vs. 7 [6-9], p value .886) in the group with a PFO with respect to the other group in which no PFO was created. In patients with TAPVC, LA can be enlarged by using a large ASD patch and thus shifting the septum towards RA. Early surgical outcomes were improved with LA enlargement. In patients with suprasystemic or high PA pressures, leaving a PFO improved the postoperative outcomes.

Vascular remodeling of the small pulmonary arteries and measures of vascular pruning on computed tomography.

Pulmonary hypertension is characterized histologically by intimal and medial thickening in the small pulmonary arteries, eventually resulting in vascular “pruning.” Computed tomography (CT)-based quantification of pruning is associated with clinical measures of pulmonary hypertension, but it is not established whether CT-based pruning correlates with histologic arterial remodeling. Our sample consisted of 138 patients who underwent resection for early-stage lung adenocarcinoma. From histologic sections, we identified small pulmonary arteries and measured the relative area comprising the intima and media (VWA%), with higher VWA% representing greater histologic remodeling. From pre-operative CTs, we used image analysis algorithms to calculate the small vessel volume fraction (BV5/TBV) as a CT-based indicator of pruning (lower BV5/TBV represents greater pruning). We investigated relationships of CT pruning and histologic remodeling using Pearson correlation, simple linear regression, and multivariable regression with adjustment for age, sex, height, weight, smoking status, and total pack-years. We also tested for effect modification by sex and smoking status. In primary models, more severe CT pruning was associated with greater histologic remodeling. The Pearson correlation coefficient between BV5/TBV and VWA% was –0.41, and in linear regression models, VWA% was 3.13% higher (95% CI: 1.95–4.31%, p < 0.0001) per standard deviation lower BV5/TBV. This association persisted after multivariable adjustment. We found no evidence that these relationships differed by sex or smoking status. Among individuals who underwent resection for lung adenocarcinoma, more severe CT-based vascular pruning was associated with greater histologic arterial remodeling. These findings suggest CT imaging may be a non-invasive indicator of pulmonary vascular pathology.

Evaluation of Right Ventricular Outflow Tract Stenting as Palliative Treatment in Severely Cyanotic Tetralogy of Fallot: A Systematic Review and Meta-Analysis of Observational Studies.

Background: Tetralogy of Fallot (ToF) is a cardiac malformation that accounts for up to 1/10 of all congenital diseases. Although surgical repair serves as a treatment of choice, it cannot be performed unless weight and anatomical key factors are favorable. The stenting of the right ventricular outflow tract (RVOT) has become an alternative palliative procedure for ToF as an option to alleviate infundibular obstruction with minimal invasion. Methods: A literature search was conducted through 7 databases, followed by the screening and independent assessment of 6 final studies, using the Newcastle-Ottawa Quality Assessment Scale (NOS). Analysis was then conducted using inverse variance analysis, and cumulative data were presented with forest and funnel plots. Results: Studied patients were referred for RVOT stenting due to the marked obstruction of the pulmonary blood flow, a low birth weight, or a small pulmonary artery size. The analysis revealed a significant increase in O2 saturation (mean difference [MD=18%; 13–23.78). The same trend was observed concerning an increase in the Nakata index (MD=54.59; 10.05–99.14), the right pulmonary artery diameter (MD=2.28; 1.20–3.36), and the left pulmonary artery diameter (MD=1.77; 0.22–3.32). Several complications were found, including tricuspid regurgitation and frequent premature beats. Conclusion: RVOT stenting is considered a feasible palliative treatment for ToF, with its high effectiveness in improving patients’ condition, especially their pulmonary flow. While complications are scarce, several conditions should be noted, particularly for fatal complications. Finally, this study has limitations as catheterization details in studies and diverse infants’ conditions may have caused potential bias

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.

Cannabinoids—A New Perspective in Adjuvant Therapy for Pulmonary Hypertension

Currently, no treatment can completely cure pulmonary hypertension (PH), which can lead to right ventricular failure and, consequently, death. Therefore, searching for new therapies remains important. Increased resistance in pulmonary circulation is mainly caused by the excessive contraction and proliferation of small pulmonary arteries. Cannabinoids, a group of lipophilic compounds that all interact with cannabinoid receptors, exert a pulmonary vasodilatory effect through several different mechanisms, including mechanisms that depend on vascular endothelium and/or receptor-based mechanisms, and may also have anti-proliferative and anti-inflammatory properties. The vasodilatory effect is important in regulating pulmonary resistance, which can improve patients’ quality of life. Moreover, experimental studies on the effects of cannabidiol (plant-derived, non-psychoactive cannabinoid) in animal PH models have shown that cannabidiol reduces right ventricular systolic pressure and excessive remodelling and decreases pulmonary vascular hypertrophy and pulmonary vascular resistance. Due to the potentially beneficial effects of cannabinoids on pulmonary circulation and PH, in this work, we review whether cannabinoids can be used as an adjunctive therapy for PH. However, clinical trials are still needed to recommend the use of cannabinoids in the treatment of PH.

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.

Regulatory effects of HIF-1α and HO-1 in hypoxia-induced proliferation of pulmonary arterial smooth muscle cells in yak

Hypoxia-inducible factor-1α (HIF-1α) and heme oxygenase-1 (HO-1) are important transcription regulators in hypoxic cells and for maintaining cellular homeostasis, but it is unclear whether they participate in hypoxia-induced excessive proliferation of yak pulmonary artery smooth muscle cells (PASMCs). In this study, we identified distribution of HIF-1α and HO-1 in yak lungs. Immunohistochemistry and immunofluorescence results revealed that both HIF-1α and HO-1 were mainly concentrated in the medial layer of small pulmonary arteries. Furthermore, under induced-hypoxic conditions, we investigated HIF-1α and HO-1 protein expression and studied their potential involvement in yak PASMCs proliferation and apoptosis. Western blot results also showed that both factors significantly increased in age-dependent manner and upregulated in hypoxic PASMCs (which exhibited obvious proliferation and anti-apoptosis phenomena). HIF-1α up-regulation by DMOG increased the proliferation and anti-apoptosis of PASMCs, while HIF-1α down-regulation by LW6 decreased proliferation and promoted apoptosis. More so, treatment with ZnPP under hypoxic conditions down-regulated HO-1 expression, stimulated proliferation, and resisted apoptosis in yak PASMCs. Taken together, our study demonstrated that both HIF-1α and HO-1 participated in PASMCs proliferation and apoptosis, suggesting that HO-1 is important for inhibition of yak PASMCs proliferation while HIF-1α promoted hypoxia-induced yak PASMCs proliferation.

Role of cardiovascular magnetic resonance in pediatric pulmonary hypertension-novel concepts and imaging biomarkers.

Pulmonary hypertension (PH) in children is a heterogenous disease of the small pulmonary arteries characterized by a progressive increase in pulmonary vascular resistance. Despite adequate medical therapy, long-term pressure overload is frequently associated with a progressive course leading to right ventricular failure and ultimately death. Invasive hemodynamic assessment by cardiac catheterization is crucial for initial diagnosis, risk stratification and therapeutic strategy. Although echocardiography remains the most important imaging modality for the assessment of right ventricular function and pulmonary hemodynamics, cardiovascular magnetic resonance (CMR) has emerged as a valuable non-invasive imaging technique that enables comprehensive evaluation of biventricular performance, blood flow, morphology and the myocardial tissue. In this review, we summarize the principles and applications of CMR in the evaluation of pediatric PH patients and present an update about novel CMR based concepts and imaging biomarkers that may provide further diagnostic, therapeutic and prognostic information.

Integrated analysis of m6A mRNA methylation in rats with monocrotaline-induced pulmonary arterial hypertension.

Background: N6-methyladenosine (m6A) modification is one of the most common chemical modifications of eukaryotic mRNAs, which play an important role in tumors and cardiovascular disease through regulating mRNA stability, splicing and translation. However, the changes of m6A mRNA and m6A-related enzymes in pulmonary arterial hypertension (PAH) remain largely unexplored.Methods: MeRIP-seq was used to identify m6A methylation in lung tissues from control and MCT-PAH rats. Western blot and immunofluorescence were used to evaluate expression of m6A-related enzymes.Results: Compared with control group, m6A methylation was mainly increased in lung tissues from MCT-PAH rats. The up-methylated coding genes in MCT-PAH rats were primarily enriched in processes associated with inflammation, glycolysis, ECM-receptor interaction and PDGF signal pathway, while genes with down-methylation were enriched in processes associated with TGF-β family receptor members. The expression of FTO and ALKBH5 downregulated, METTL3 and YTHDF1 increased and other methylation modification-related proteins was not significantly changed in MCT-PAH rats lung tissues. Immunofluorescence indicated that expression of FTO decreased and YTHDF1 increased in small pulmonary arteries of MCT-PAH rats.Conclusion: m6A levels and the expression of methylation-related enzymes were altered in PAH rats, in which FTO and YTHDF1 may play a crucial role in m6A modification.

Reverse remodeling of small pulmonary arteries and right ventricle in pulmonary arterial hypertension

Reverse remodeling of small pulmonary arteries and right ventricle in pulmonary arterial hypertension

Outcomes of surgical reconstruction of the superior vena cava syndrome in patients with locally advanced thymomas

The aim of the study: to study and demonstrate the potential and technical aspects of the surgical treatment of locally advanced thymus tumours with the tumour infiltrate affecting superior vena cava and its branches.&#x0D; Methods. 56 patients with locally advanced thymomas complicated by SVCS were study. The control group included 30 patients with SVCS were treated with conventional techniques, while the experimental group included 26 patients who underwent a novel bypass surgery developed by us.&#x0D; Results. Based on our observations, patients tolerated these surgeries much better. The venous bypass was mandatorily complemented with cytoreduction. Auriculo-jugular (left and right) and auriculo-subclavian (left and right) bypasses were used in our observations&#x0D; Complications in the post-operative period were reported from the experimental group and included auriculo-subclavian bypass thrombosis, post-operative complications were reported in the control group including haemorrhage from the sternotomy wound in 1 (3.3 %) case, superior vena cava thrombosis in 2 (6.6 %) cases, pneumonia in 2 (6.6 %) cases and thromboembolism of small pulmonary arteries in 2 (6.6 %) cases.&#x0D; Post-operative lethality in the study groups was reported in the control and in the experimental group. Total lethality rate was 8.9 % (5 patients). The relative risk of complications and lethal outcome was calculated for patients from both groups. It was found that the risk of complications was twice as high in the control group as in the experimental group (standard error of relative risk equals 0.64), whereas the risk of lethal outcome increased by a factor of 3.5 in the control group (standard error of relative risk equals 1.09)&#x0D; Conclusion. It has been established that the superior vena cava syndrome in patients with locally advanced thymoma is an emergency condition whose surgical correction must be personalised depending on the anatomic and topographic classification of SVC lesion types. It is known that an obligatory pre-condition of the perioperative period in this category of patients is an adequate vascular approach to the superior vena cava system. The first mandatory step of the radical surgery in patients with locally advanced thymomas with SVC invasion should be the auriculo-jugular and auriculo-subclavian bypasses, which can reduce the relative risk of post-operative complications by a factor of the risk of lethal by a factor of 3.5.

Bioactive Compounds From Coptidis Rhizoma Alleviate Pulmonary Arterial Hypertension by Inhibiting Pulmonary Artery Smooth Muscle Cells' Proliferation and Migration.

Pulmonary arterial hypertension (PAH) is a devastating disorder characterized by excessive proliferation and vasoconstriction of small pulmonary artery vascular smooth muscle cells (PASMCs). Coptidis rhizoma (CR) because of the complexity of the components, the underlying pharmacological role and mechanism of it on PAH remains unknown. In this article, the network pharmacological analysis was used to screen the main active constituents of CR and the molecular targets that these constituents act on. Then, we evaluated the importance of berberine and quercetin (biologically active components of CR) on the proliferation and migration of PASMCs and vascular remodeling in experimental models of PAH. Our results showed that berberine and quercetin effectively inhibited the proliferation and migration of hypoxia-induced PASMCs in a manner likely to be mediated by the suppression of MAPK1, NADPH oxidase 4 (NOX4), and cytochrome P450 1B1 (CYP1B1) expression. Furthermore, berberine and quercetin treatment attenuates pulmonary hypertension, reduces right ventricular hypertrophy, and improves pulmonary artery remodeling in monocrotaline-induced pulmonary hypertension in rat models. In conclusion, this research demonstrates CR might be a promising treatment option for PAH, and the network pharmacology approach can be an effective tool to reveal the potential mechanisms of Chinese herbal medicine.

Endogenous Endothelin‐1 Contributes to Enhanced Basal Pulmonary Arterial Tone Following Chronic Hypoxia: Role of Mitochondria‐Derived Reactive Oxygen Species

Previous studies from our laboratory demonstrate the importance of mitochondria-derived reactive oxygen species (mitoROS) in the development of pulmonary hypertension after chronic hypoxia (CH) exposure. Furthermore, we have identified a major role for the endothelium to augment mitoROS-dependent pulmonary vascular tone following CH. However, the mechanism of this response remains unclear. We hypothesized that the endogenous vasoconstrictor peptide, endothelin-1 (ET-1), facilitates mitoROS-dependent increases in basal tone after CH exposure. To test our hypothesis, we measured basal tone by videomicroscopy in isolated, pressurized, small pulmonary arteries [~150 μm inner diameter (i.d.)] from normoxic and CH (4 wk, 0.5 atm) rats with and without the ETA receptor and ETB receptor inhibitors, BQ123 and BQ788 (10 μM each), respectively. Parallel protocols were conducted in the presence of the mitochondria-targeted antioxidant, MitoQ (1 μM). All experiments were performed in the presence of the nitric oxide (NO) synthase inhibitor, Nω-nitro-L-arginine (300 μM), to limit the influence of endogenous NO. Pulmonary arterial tone was calculated as the percent difference in i.d. between Ca2+-free and Ca2+-containing conditions. To evaluate the contribution of mitoROS to ET-1-mediated vasoconstriction, we further assessed vasoconstrictor responses (percentage of baseline i.d.) to serial concentrations of exogenous ET-1 (10-11 to 10-7 M) in the presence or absence of MitoQ in endothelium-disrupted pulmonary arteries from each group. Additional experiments employed confocal microscopy to measure ET-1 (1 nM)-induced mitoROS production in primary cultures of pulmonary arterial smooth muscle cells (PASMCs) from control and CH rats using the fluorescent mitochondrial superoxide indicator MitoSOX (10 μM). Antimycin A (10 µM) treatment, which stimulates mitoROS production from complex III of electron transport chain, was used as a positive control. Both MitoQ and the combined administration of ETA and ETB receptor blockers abolished the effect of CH to increase basal tone (P<0.05). Arteries from CH rats also exhibited greater constriction to exogenous ET-1 (at 1 nM) compared to vessels from normoxic controls, which was prevented by MitoQ (P<0.05). Consistent with these findings, application of ET-1 significantly increased mitoROS production in PASMCs from CH rats (P<0.05), but not control animals. Application of antimycin A led to mitoROS generation in both control and CH groups (P<0.05). We conclude that endogenous ET-1 promotes pulmonary arterial constriction through mitoROS signaling in PASMCs following CH. These findings advance our understanding of the mechanistic basis for the vasoconstrictor component of CH-induced pulmonary hypertension.

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

Endothelial cells (EC) dilate small pulmonary arteries (PAs) and lower the resting pulmonary arterial pressure (PAP). Moreover, the loss of endothelial function is a key contributor to elevated PAP in pulmonary hypertension. Therefore, an in-depth understanding of endothelial mechanisms controlling PAP is necessary for designing novel therapeutic strategies against pulmonary hypertension. Pannexin 1 (Panx1), an ATP efflux pathway on the EC membranes, has emerged as a crucial controller of endothelial function. However, the impact of endothelial Panx1 (Panx1EC) on PA contractility and PAP is not known. Recent studies support the idea that endothelial transient receptor potential vanilloid 4 (TRPV4EC) channels dilate small PAs, and are activated by extracellular ATP (eATP). Since Panx1EC is an ATP efflux pathway, we hypothesized that Panx1EC-TRPV4EC channel signaling dilates PAs and lowers resting PAP. Right ventricular systolic pressure (RVSP), an indirect indicator of PAP, was higher in inducible, EC-specific Panx1 (Panx1EC-/-) and TRPV4 channel knockout (TRPV4EC-/-) mice compared to the respective control mice. The activity of TRPV4EC channels was recorded as individual Ca2+ influx signals (TRPV4EC sparklets) in fluo 4-loaded en face PAs using spinning disk confocal imaging. The TRPV4EC sparklet activity was lower in PAs from Panx1EC-/- mice than the control mice, identifying Panx1EC as a novel promoter of TRPV4EC channel activity. Apyrase (10 U/mL), an ATP hydrolyzing enzyme, also reduced the activity of TRPV4EC sparklets in PAs from control mice but not Panx1EC-/- mice. Pressurized PAs (15 mm Hg) from Panx1EC-/- and TRPV4EC-/- mice showed higher constriction to thromboxane A2 receptor agonist U46619 (1-300 nM) compared to PAs from the respective control mice. These data indicated that Panx1EC-eATP-TRPV4EC signaling lowers PA contractility and PAP. Consistent with previous findings that eATP dilates PAs via purinergic P2Y2 receptor (P2Y2R) signaling, ATP activation of TRPV4EC channels was lost in PAs from inducible P2Y2EC-/- mice. Together, these data identify a novel Panx1EC-eATP-P2Y2REC signaling pathway that promotes TRPV4EC channel activity in PAs. Panx1, P2Y2R, and TRPV4 channels have been shown to localize with the scaffolding protein caveolin 1 (Cav-1), raising the possibility that Cav-1EC may provide a signaling scaffold for Panx1EC-P2Y2REC-TRPV4EC signaling in PAs. Accordingly, P2Y2REC-activation of TRPV4EC channels was lost in PAs from inducible Cav-1EC-/- mice, and these mice showed higher resting RVSPs compared to the control mice. Additionally, in situ proximity ligation assay confirmed the nanometer proximity of Cav-1EC with Panx1EC, P2Y2REC, and TRPV4EC channel in PAs. Overall, our findings identify Cav-1EC-dependent Panx1EC-P2Y2REC-TRPV4EC channel pathway that dilates PAs and lowers PAP. Targeting individual elements of this pathway may provide novel therapeutic options in pulmonary vascular disorders.