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Mircea Gabriel Stoleriu,1,2,&ast; Michael Pienn,3,4,&ast; Rudolf A Joerres,5 Peter Alter,6 Tamas Fero,7 Martin Urschler,8 Gabor Kovacs,3,9 Horst Olschewski,3,9 Hans-Ulrich Kauczor,7,10 Mark Wielpütz,7,10 Bertram Jobst,7,10 Tobias Welte,11 Jürgen Behr,2,12 Franziska C Trudzinski,10,13 Robert Bals,14,15 Henrik Watz,16 Claus F Vogelmeier,6 Jürgen Biederer,10,17,18,&ast; Kathrin Kahnert2,12,19,&ast; On behalf of the COSYCONET Study Group1Division for Thoracic Surgery Munich, Ludwig-Maximilians-University of Munich (LMU) and Asklepios Medical Center; Munich-Gauting, Gauting, 82131, Germany; 2Institute for Lung Health and Immunity and Comprehensive Pneumology Center with the CPC-M bioArchive; Helmholtz Center Munich; Member of the German Lung Research Center (DZL), Munich, 81377, Germany; 3Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; 4Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; 5Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Hospital of Ludwig-Maximilians-University Munich (LMU), Munich, 80336, Germany; 6Department of Medicine, Pulmonary and Critical Care Medicine, University of Marburg (UMR), Member of the German Center for Lung Research (DZL), Marburg, 35033, Germany; 7Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany; 8Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria; 9University Clinic for Internal Medicine, Medical University of Graz, Division of Pulmonology, Graz, Austria; 10Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research DZL, Heidelberg, Germany; 11Department of Respiratory Medicine and Infectious Disease, Member of the German Center of Lung Research, Hannover School of Medicine, Hannover, Germany; 12Department of Medicine V, LMU University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany; 13Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Heidelberg, Germany; 14Department of Internal Medicine V-Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg, 66421, Germany; 15Helmholtz Institute for Pharmaceutical Research, Saarbrücken, 66123, Germany; 16Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Centre North, German Centre for Lung Research, Großhansdorf, Germany; 17Faculty of Medicine, Christian-Albrechts-Universität Zu Kiel, Kiel, Germany; 18University of Latvia, Faculty of Medicine, Riga, LV-1586, Latvia; 19MediCenterGermering, Germering, Germany&ast;These authors contributed equally to this workCorrespondence: Mircea Gabriel Stoleriu, Division of Thoracic Surgery Munich, Ludwig-Maximilians-University of Munich (LMU) and Asklepios Lung Clinic Munich-Gauting, Marchioninistr. 15, 81377 Munich and Robert-Koch-Allee 2, Gauting, 82131, Germany, Tel +49 89 85791 4201, Email gabriel.stoleriu@helmholtz-munich.dePurpose: The aim of this study was to evaluate the association between computed tomography (CT) quantitative pulmonary vessel morphology and lung function, disease severity, and mortality risk in patients with chronic obstructive pulmonary disease (COPD).Patients and Methods: Participants of the prospective nationwide COSYCONET cohort study with paired inspiratory-expiratory CT were included. Fully automatic software, developed in-house, segmented arterial and venous pulmonary vessels and quantified volume and tortuosity on inspiratory and expiratory scans. The association between vessel volume normalised to lung volume and tortuosity versus lung function (forced expiratory volume in 1 sec [FEV1]), air trapping (residual volume to total lung capacity ratio [RV/TLC]), transfer factor for carbon monoxide (TLCO), disease severity in terms of Global Initiative for Chronic Obstructive Lung Disease (GOLD) group D, and mortality were analysed by linear, logistic or Cox proportional hazard regression.Results: Complete data were available from 138 patients (39% female, mean age 65 years). FEV1, RV/TLC and TLCO, all as % predicted, were significantly (p < 0.05 each) associated with expiratory vessel characteristics, predominantly venous volume and arterial tortuosity. Associations with inspiratory vessel characteristics were absent or negligible. The patterns were similar for relationships between GOLD D and mortality with vessel characteristics. Expiratory venous volume was an independent predictor of mortality, in addition to FEV1.Conclusion: By using automated software in patients with COPD, clinically relevant information on pulmonary vasculature can be extracted from expiratory CT scans (although not inspiratory scans); in particular, expiratory pulmonary venous volume predicted mortality.Trial Registration: NCT01245933.Keywords: COPD, computed tomography, pulmonary vasculature, vessel volume, vessel tortuosity, lung function

Vascular cell overgrowth and lumen size reduction in pulmonary vein stenosis (PVS) can result in elevated PV pressure, pulmonary hypertension, cardiac failure, and death. Administration of chemotherapies such as rapamycin have shown promise by inhibiting the vascular cell proliferation; yet clinical success is limited due to complications such as restenosis and off‐target effects. The lack of in vitro models to recapitulate the complex pathophysiology of PVS has hindered the identification of disease mechanisms and therapies. This study integrated 3D bioprinting, functional nanoparticles, and perfusion bioreactors to develop a novel in vitro model of PVS. Bioprinted bifurcated PV constructs are seeded with endothelial cells (ECs) and perfused, demonstrating the formation of a uniform and viable endothelium. Computational modeling identified the bifurcation point at high risk of EC overgrowth. Application of an external magnetic field enabled targeting of the rapamycin‐loaded superparamagnetic iron oxide nanoparticles at the bifurcation site, leading to a significant reduction in EC proliferation with no adverse side effects. These results establish a 3D bioprinted in vitro model to study PV homeostasis and diseases, offering the potential for increased throughput, tunability, and patient specificity, to test new or more effective therapies for PVS and other vascular diseases. [ABSTRACT FROM AUTHOR]

Northern pulmonary hypertension (NPH) is a medical condition that is still enigmatic in non-Russian-speaking countries. The extant previous literature is mostly available in the Russian language and, therefore, not accessible to the rest of the world. The recent increased interest in climate changes and environmental effects on pulmonary circulation prompted us to summarize the knowledge from the past about the effects of cold on pulmonary vasculature. In this review, we, for the first time, describe, in detail, the pathological attributes of human NPH, a medical disorder that occurs in people living in extremely cold regions, in the English language. Briefly, NPH is characterized by the hyper-muscularization of the pulmonary arteries and de novo muscularization of the arterioles with the ultimate development of right ventricular hypertrophy. However, the profound molecular mechanisms of the NPH pathology are to be revealed in future comprehensive studies. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is an inherited disorder caused by a deleterious mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Given that the CFTR protein is a chloride channel expressed on a variety of cells throughout the human body, mutations in this gene impact several organs, particularly the lungs. For this very reason, research regarding CF disease and CFTR function has historically focused on the lung airway epithelium. Nevertheless, it was discovered more than two decades ago that CFTR is also expressed and functional on endothelial cells. Despite the great strides that have been made in understanding the role of CFTR in the airway epithelium, the role of CFTR in the endothelium remains unclear. Considering that the airway epithelium and endothelium work in tandem to allow gas exchange, it becomes very crucial to understand how a defective CFTR protein can impact the pulmonary vasculature and overall lung function. Fortunately, more recent research has been dedicated to elucidating the role of CFTR in the endothelium. As a result, several vascular dysfunctions associated with CF disease have come to light. Here, we summarize the current knowledge on pulmonary vascular dysfunctions in CF and discuss applicable therapies. [ABSTRACT FROM AUTHOR]

Subtle changes in the membrane potential of pulmonary arterial smooth muscle cells (PASMCs) are pivotal for controlling pulmonary vascular tone, e.g., for initiating Hypoxic Pulmonary Vasoconstriction, a vital mechanism of the pulmonary circulation. In our study, we evaluated the ability of the fluorescence resonance energy transfer (FRET)-based voltage-sensor Mermaid to detect such subtle changes in membrane potential. Mouse PASMCs were isolated and transduced with Mermaid-encoding lentiviral vectors before the acceptor/donor emission ratio was assessed via live cell FRET-imaging. Mermaid's sensitivity was tested by applying specific potassium chloride (KCl) concentrations. These KCl concentrations were previously validated by patch clamp recordings to induce depolarization with predefined amplitudes that physiologically occur in PASMCs. Mermaid's emission ratio dose-dependently increased upon depolarization with KCl. However, Mermaid formed unspecific intracellular aggregates, which limited the usefulness of this voltage sensor. When analyzing the membrane rim only to circumvent these unspecific signals, Mermaid was not suitable to resolve subtle changes in the membrane potential of ≤10 mV. In summary, we found Mermaid to be a suitable alternative for reliably detecting qualitative membrane voltage changes of more than 10 mV in primary mouse PASMCs. However, one should be aware of the limitations associated with this voltage sensor. [ABSTRACT FROM AUTHOR]

The mitochondrial adaptor protein p66Shc has been suggested to control life span in mice via the release of hydrogen peroxide. However, the role of p66Shc in lung aging remains unsolved. Thus, we investigated the effects of p66Shc-/- on the aging of the lung and pulmonary circulation. In vivo lung and cardiac characteristics were investigated in p66Shc-/- and wild type (WT) mice at 3, 12, and 24 months of age by lung function measurements, micro-computed tomography (μCT), and echocardiography. Alveolar number and muscularization of small pulmonary arteries were measured by stereology and vascular morphometry, respectively. Protein and mRNA levels of senescent markers were measured by western blot and PCR, respectively. Lung function declined similarly in WT and p66Shc-/- mice during aging. However, μCT analyses and stereology showed slightly enhanced signs of agingrelated parameters in p66Shc-/- mice, such as a decline of alveolar density. Accordingly, p66Shc-/- mice showed higher protein expression of the senescence marker p21 in lung homogenate compared to WT mice of the corresponding age. Pulmonary vascular remodeling was increased during aging, but aged p66Shc-/- mice showed similar muscularization of pulmonary vessels and hemodynamics like WT mice. In the heart, p66Shc-/- prevented the deterioration of right ventricular (RV) function but promoted the decline of left ventricular (LV) function during aging. p66Shc-/- affects the aging process of the lung and the heart differently. While p66Shc-/- slightly accelerates lung aging and deteriorates LV function in aged mice, it seems to exert protective effects on RV function during aging. [ABSTRACT FROM AUTHOR]

Abstract Vascular cell overgrowth and lumen size reduction in pulmonary vein stenosis (PVS) can result in elevated PV pressure, pulmonary hypertension, cardiac failure, and death. Administration of chemotherapies such as rapamycin have shown promise by inhibiting the vascular cell proliferation; yet clinical success is limited due to complications such as restenosis and off‐target effects. The lack of in vitro models to recapitulate the complex pathophysiology of PVS has hindered the identification of disease mechanisms and therapies. This study integrated 3D bioprinting, functional nanoparticles, and perfusion bioreactors to develop a novel in vitro model of PVS. Bioprinted bifurcated PV constructs are seeded with endothelial cells (ECs) and perfused, demonstrating the formation of a uniform and viable endothelium. Computational modeling identified the bifurcation point at high risk of EC overgrowth. Application of an external magnetic field enabled targeting of the rapamycin‐loaded superparamagnetic iron oxide nanoparticles at the bifurcation site, leading to a significant reduction in EC proliferation with no adverse side effects. These results establish a 3D bioprinted in vitro model to study PV homeostasis and diseases, offering the potential for increased throughput, tunability, and patient specificity, to test new or more effective therapies for PVS and other vascular diseases.

While computed tomography pulmonary angiography (CTPA) is an integral part of the work-up in patients with suspected pulmonary hypertension (PH), there is no established CTPA-derived prognostic marker. We aimed to assess whether quantitative readouts of lung vessel morphology correlate with established prognostic indicators in PH. We applied a fully-automatic in-house developed algorithm for segmentation of arteries and veins to determine lung vessel morphology in patients with precapillary PH who underwent right heart catheterization and CTPA between May 2016 and May 2019. Primary endpoint of this retrospective study was the calculation of receiver operating characteristics for identifying low and high mortality risk according to the 3-strata risk assessment model presented in the current guidelines. We analyzed 73 patients, median age 65 years (interquartile range (IQR): 54-76), female/male ratio 35/38, median mean pulmonary arterial pressure 37 mm Hg (IQR: 30-46), and found significant correlations with important prognostic factors in pulmonary arterial hypertension. N-terminal pro-brain natriuretic peptide, cardiac index, mixed venous oxygen saturation, and 6-minute walking distance were correlated with the ratio of the number of arteries over veins with vessel diameters of 6-10 mm (Spearman correlation coefficients ρ = 0.64, p < 0.001; ρ = −0.60, p < 0.001; ρ = −0.47, p = 0.005; ρ = −0.45, p = 0.001, respectively). This ratio predicted a low- and high-risk score with an area under the curve of 0.73 (95% confidence interval (CI): 0.56-0.90) and 0.86 (95% CI: 0.74-0.97), respectively. The ratio of the number of arteries over veins with diameters between 6 and 10 mm is significantly correlated with prognostic markers in pulmonary hypertension and predicts low and high mortality risk. [ABSTRACT FROM AUTHOR]

Abstract Background Hydatid disease is a parasitic infection which is endemic in multiple regions across the globe including Indian subcontinent. Although it commonly affects the liver and other solid organs, isolated involvement of the heart is relatively uncommon. Cardiac hydatidosis can be confidently diagnosed on echocardiography, but cross-sectional imaging by computed tomography (CT) or magnetic resonance imaging (MRI) provides accurate information about its location, extent, and multiplicity. Multiple case studies of cardiac hydatid disease have been reported in the literature. However, cardiac hydatidosis with extension into pulmonary vasculature has not been reported commonly. This case report highlights this rare association, with stress upon the altered surgical management. Case presentation A 50-year-old patient presented with atypical chest pain to the cardiology department of a tertiary care hospital where he underwent multiple blood tests as well as electrocardiography (ECG) and echocardiography as part of the routine examination. Echocardiography revealed a large, multicystic mass invading the posterolateral wall of left ventricle (LV) with no internal vascularity and was provisionally diagnosed as hydatid disease. Subsequent CT study confirmed a large multicystic lesion with the presence of another smaller lesion invading the left atrial appendage (LAA). In order to evaluate the vascular and mediastinal invasion, cardiac MRI was then performed which revealed invasion of right pulmonary artery (PA), right superior pulmonary vein (PV) as well as compression of superior vena cava (SVC) by the smaller lesion. A final diagnosis of cardiac hydatidosis with invasion into right PA and right superior PV was made. Treatment plan for the patient changed, who then underwent an additional reconstruction of right PA and right superior PV after cyst removal. Conclusions Cardiac hydatid disease is a rare but potentially lethal condition, which tends to show slow growth and local invasion. The diversity of findings in such rare cases makes individual surgical approach extremely valuable with preoperative radiological imaging becoming indispensable for correct localization and appropriate planning. Our case report highlights rare association of cardiac hydatidosis with invasion of both pulmonary artery and vein, which eventually altered the surgical management of patient.

Northern pulmonary hypertension (NPH) is a medical condition that is still enigmatic in non-Russian-speaking countries. The extant previous literature is mostly available in the Russian language and, therefore, not accessible to the rest of the world. The recent increased interest in climate changes and environmental effects on pulmonary circulation prompted us to summarize the knowledge from the past about the effects of cold on pulmonary vasculature. In this review, we, for the first time, describe, in detail, the pathological attributes of human NPH, a medical disorder that occurs in people living in extremely cold regions, in the English language. Briefly, NPH is characterized by the hyper-muscularization of the pulmonary arteries and de novo muscularization of the arterioles with the ultimate development of right ventricular hypertrophy. However, the profound molecular mechanisms of the NPH pathology are to be revealed in future comprehensive studies.

Subtle changes in the membrane potential of pulmonary arterial smooth muscle cells (PASMCs) are pivotal for controlling pulmonary vascular tone, e.g., for initiating Hypoxic Pulmonary Vasoconstriction, a vital mechanism of the pulmonary circulation. In our study, we evaluated the ability of the fluorescence resonance energy transfer (FRET)-based voltage-sensor Mermaid to detect such subtle changes in membrane potential. Mouse PASMCs were isolated and transduced with Mermaid-encoding lentiviral vectors before the acceptor/donor emission ratio was assessed via live cell FRET-imaging. Mermaid’s sensitivity was tested by applying specific potassium chloride (KCl) concentrations. These KCl concentrations were previously validated by patch clamp recordings to induce depolarization with predefined amplitudes that physiologically occur in PASMCs. Mermaid’s emission ratio dose-dependently increased upon depolarization with KCl. However, Mermaid formed unspecific intracellular aggregates, which limited the usefulness of this voltage sensor. When analyzing the membrane rim only to circumvent these unspecific signals, Mermaid was not suitable to resolve subtle changes in the membrane potential of ≤10 mV. In summary, we found Mermaid to be a suitable alternative for reliably detecting qualitative membrane voltage changes of more than 10 mV in primary mouse PASMCs. However, one should be aware of the limitations associated with this voltage sensor.

Background: Hydatid disease is a parasitic infection which is endemic in multiple regions across the globe including Indian subcontinent. Although it commonly affects the liver and other solid organs, isolated involvement of the heart is relatively uncommon. Cardiac hydatidosis can be confidently diagnosed on echocardiography, but cross-sectional imaging by computed tomography (CT) or magnetic resonance imaging (MRI) provides accurate information about its location, extent, and multiplicity. Multiple case studies of cardiac hydatid disease have been reported in the literature. However, cardiac hydatidosis with extension into pulmonary vasculature has not been reported commonly. This case report highlights this rare association, with stress upon the altered surgical management. Case presentation: A 50-year-old patient presented with atypical chest pain to the cardiology department of a tertiary care hospital where he underwent multiple blood tests as well as electrocardiography (ECG) and echocardiography as part of the routine examination. Echocardiography revealed a large, multicystic mass invading the posterolateral wall of left ventricle (LV) with no internal vascularity and was provisionally diagnosed as hydatid disease. Subsequent CT study confirmed a large multicystic lesion with the presence of another smaller lesion invading the left atrial appendage (LAA). In order to evaluate the vascular and mediastinal invasion, cardiac MRI was then performed which revealed invasion of right pulmonary artery (PA), right superior pulmonary vein (PV) as well as compression of superior vena cava (SVC) by the smaller lesion. A final diagnosis of cardiac hydatidosis with invasion into right PA and right superior PV was made. Treatment plan for the patient changed, who then underwent an additional reconstruction of right PA and right superior PV after cyst removal. Conclusions: Cardiac hydatid disease is a rare but potentially lethal condition, which tends to show slow growth and local invasion. The diversity of findings in such rare cases makes individual surgical approach extremely valuable with preoperative radiological imaging becoming indispensable for correct localization and appropriate planning. Our case report highlights rare association of cardiac hydatidosis with invasion of both pulmonary artery and vein, which eventually altered the surgical management of patient. [ABSTRACT FROM AUTHOR]

Lungs are constantly exposed to environmental perturbations and therefore have remarkable capacity to regenerate in response to injury. Sustained lung injuries, aging, and increased genomic instability, however, make lungs particularly susceptible to disrepair and fibrosis. Pulmonary fibrosis constitutes a major cause of morbidity and is often relentlessly progressive, leading to death from respiratory failure. The pulmonary vasculature, which is critical for gas exchanges and plays a key role during lung development, repair, and regeneration, becomes aberrantly remodeled in patients with progressive pulmonary fibrosis. Although capillary rarefaction and increased vascular permeability are recognized as distinctive features of fibrotic lungs, the role of vasculature dysfunction in the pathogenesis of pulmonary fibrosis has only recently emerged as an important contributor to the progression of this disease. This review summarizes current findings related to lung vascular repair and regeneration and provides recent insights into the vascular abnormalities associated with the development of persistent lung fibrosis. [ABSTRACT FROM AUTHOR]

ABSTRACT Nitric oxide (NO) is an important mediator responsible for vasodilation in pulmonary hypertension (PH) in humans. Based on human literature, it is suggested that in dogs there is also NO production decrease in lung tissue in the presence of PH with hypoxia. Therefore, the aim of this research was to determine the indirect plasmatic NO concentration in dogs with PH secondary or not to the left-side heart disease (LHD) and also with low, intermediate and high probability of PH to characterize the NO involvement on PH in dogs. Blood samples were collected from 35 dogs with probability of PH to NO measurement. NO concentration was estimated by the nitrite/nitrate concentration, and it was significantly different (p=0.002) in dogs with PH secondary to LHD (median=14 µM, range 11.19-16.59) and not secondary to LHD (median=25.88µM, range 15.08-36.71). However, this was not significant for the probability of low, intermediate, and high PH, although there was a tendency for NO concentration to be higher in dogs with high PH. The results of this study demonstrate that there is release of NO in dogs with PH, as well as that its dosage could differentiate dogs with PH secondary to LHD from dogs with non-secondary PH.

The mammalian pulmonary vasculature consists of functionally and morphologically heterogeneous compartments. When comparing sets of lungs, for example, in disease models or therapeutic interventions, local changes may be masked by the overall heterogeneity of the organ structure. Therefore, alterations taking place only in a sub‐compartment may not be detectable by global analysis. In the monopodial lung, the characterization of distinct vessel groups is difficult, due to the asymmetrical branching pattern. In this pilot study, a previously established method to classify segments of the monopodial pulmonary arterial tree into homogeneous groups was employed. To test its suitability for experimental settings, the method was applied to a hyperoxia (HYX, ≥95% oxygen) rabbit model of bronchopulmonary dysplasia and a normoxic control group (NOX, 21% oxygen). The method allowed the identification of morphological differences between the HYX and the NOX groups. Globally visible differences in lumen diameter were pinpointed to specific lung regions. Furthermore, local changes of wall dimension and cell layers in single compartments, that would not have been identifiable in an unfocused analysis of the whole dataset, were found. In conclusion, the described method achieves a higher precision in morphological studies of lung disease models, compared to a common, global analysis approach. [ABSTRACT FROM AUTHOR]

Intracellular Ca2+ signals are key for the regulation of cellular processes ranging from myocyte contraction, hormonal secretion, neural transmission, cellular metabolism, transcriptional regulation, and cell proliferation. Measurement of cellular Ca2+ is routinely performed using fluorescence microscopy with biological indicators. Analysis of deterministic signals is reasonably straightforward as relevant data can be discriminated based on the timing of cellular responses. However, analysis of stochastic, slower oscillatory events, as well as rapid subcellular Ca2+ responses, takes considerable time and effort which often includes visual analysis by trained investigators, especially when studying signals arising from cells embedded in complex tissues. The purpose of the current study was to determine if full-frame time-series and line-scan image analysis workflow of Fluo-4 generated Ca2+ fluorescence data from vascular myocytes could be automated without introducing errors. This evaluation was addressed by re-analyzing a published "gold standard" full-frame time-series dataset through visual analysis of Ca2+ signals from recordings made in pulmonary arterial myocytes of en face arterial preparations. We applied a combination of data driven and statistical approaches with comparisons to our published data to assess the fidelity of the various approaches. Regions of interest with Ca2+ oscillations were detected automatically post hoc using the LCPro plug-in for ImageJ. Oscillatory signals were separated based on event durations between 4 and 40 s. These data were filtered based on cutoffs obtained from multiple methods and compared to the published manually curated "gold standard" dataset. Subcellular focal and rapid Ca2+ "spark" events from line-scan recordings were examined using SparkLab 5.8, which is a custom automated detection and analysis program. After filtering, the number of true positives, false positives, and false negatives were calculated through comparisons to visually derived "gold standard" datasets. Positive predictive value, sensitivity, and false discovery rates were calculated. There were very few significant differences between the automated and manually curated results with respect to quality of the oscillatory and Ca2+ spark events, and there were no systematic biases in the data curation or filtering techniques. The lack of statistical difference in event quality between manual data curation and statistically derived critical cutoff techniques leads us to believe that automated analysis techniques can be reliably used to analyze spatial and temporal aspects to Ca2+ imaging data, which will improve experiment workflow. [ABSTRACT FROM AUTHOR]

Transmembrane protein 100 (TMEM100) is a crucial factor in the development and maintenance of the vascular system. The protein is involved in several processes such as angiogenesis, vascular morphogenesis, and integrity. Furthermore, TMEM100 is a downstream target of the BMP9/10 and BMPR2/ALK1 signaling pathways, which are key regulators of vascular development. Our recent studies have shown that TMEM100 is a lung endothelium enriched gene and plays a significant role in lung vascular repair and regeneration. The importance of TMEM100 in endothelial cells' regeneration was demonstrated when Tmem100 was specifically deleted in endothelial cells, causing an impairment in their regenerative ability. However, the role of TMEM100 in various conditions and diseases is still largely unknown, making it an interesting area of research. This review summarizes the current knowledge of TMEM100, including its expression pattern, function, molecular signaling, and clinical implications, which could be valuable in the development of novel therapies for the treatment of cardiovascular and pulmonary diseases. [ABSTRACT FROM AUTHOR]

Aberrant vascular remodeling contributes to the progression of many aging-associated diseases, including idiopathic pulmonary fibrosis (IPF), where heterogeneous capillary density, endothelial transcriptional alterations, and increased vascular permeability correlate with poor disease outcomes. Thus, identifying disease-driving mechanisms in the pulmonary vasculature may be a promising strategy to limit IPF progression. Here, we identified Ccn3 as an endothelial-derived factor that is upregulated in resolving but not in persistent lung fibrosis in mice, and whose function is critical for vascular homeostasis and repair. Loss and gain of function experiments were carried out to test the role of CCN3 in lung microvascular endothelial function in vitro through RNAi and the addition of recombinant human CCN3 protein, respectively. Endothelial migration, permeability, proliferation, and in vitro angiogenesis were tested in cultured human lung microvascular endothelial cells (ECs). Loss of CCN3 in lung ECs resulted in transcriptional alterations along with impaired wound-healing responses, in vitro angiogenesis, barrier integrity as well as an increased profibrotic activity through paracrine signals, whereas the addition of recombinant CCN3 augmented endothelial function. Altogether, our results demonstrate that the matricellular protein CCN3 plays an important role in lung endothelial function and could serve as a promising therapeutic target to facilitate vascular repair and promote lung fibrosis resolution. [ABSTRACT FROM AUTHOR]

Abstract The mammalian pulmonary vasculature consists of functionally and morphologically heterogeneous compartments. When comparing sets of lungs, for example, in disease models or therapeutic interventions, local changes may be masked by the overall heterogeneity of the organ structure. Therefore, alterations taking place only in a sub‐compartment may not be detectable by global analysis. In the monopodial lung, the characterization of distinct vessel groups is difficult, due to the asymmetrical branching pattern. In this pilot study, a previously established method to classify segments of the monopodial pulmonary arterial tree into homogeneous groups was employed. To test its suitability for experimental settings, the method was applied to a hyperoxia (HYX, ≥95% oxygen) rabbit model of bronchopulmonary dysplasia and a normoxic control group (NOX, 21% oxygen). The method allowed the identification of morphological differences between the HYX and the NOX groups. Globally visible differences in lumen diameter were pinpointed to specific lung regions. Furthermore, local changes of wall dimension and cell layers in single compartments, that would not have been identifiable in an unfocused analysis of the whole dataset, were found. In conclusion, the described method achieves a higher precision in morphological studies of lung disease models, compared to a common, global analysis approach.

Mammalian pulmonary arteries divide multiple times before reaching the vast capillary network of the alveoli. Morphological analyses of the arterial branches can be challenging because more proximal branches are likely biologically distinct from more peripheral parts. Thus, it is useful to group the arterial branches into groups of coherent biology. While the generational approach of dichotomous branching is straightforward, the grouping of arterial branches in the asymmetrically branching monopodial lung is less clear. Several established classification methods return highly dissimilar groupings when employed on the same organ. Here, we established a workflow allowing the quantification of grouping results for the monopodial lung and tested various methods to group the branches of the arterial tree into coherent groups. A mouse lung was imaged by synchrotron x-ray microcomputed tomography, and the arteries were digitally segmented. The arterial tree was divided into its individual segments, morphological properties were assessed from corresponding light microscopic scans, and different grouping methods were employed, such as (fractal) generation or (Strahler) order. The results were ranked by the morphological similarity within and dissimilarity between the resulting groups. Additionally, a method from the mathematical field of cluster analysis was employed for creating a reference classification. In conclusion, there were significant differences in method performance. The Strahler order was significantly superior to the generation system commonly used to classify human lung structure. Furthermore, a clustering approach indicated more precise ways to classify the monopodial lung vasculature exist. [ABSTRACT FROM AUTHOR]

Our respiratory system is exposed to toxicants and pathogens from both sides: the airways and the vasculature. While tracheal, bronchial and alveolar epithelial cells form a natural barrier in the airways, endothelial cells protect the lung from perfused toxic compounds, particulate matter and invading microorganism in the vascular system. Damages induce inflammation by our immune response and wound healing by (myo)fibroblast proliferation. Members of the transient receptor potential (TRP) superfamily of ion channel are expressed in many cells of the respiratory tract and serve multiple functions in physiology and pathophysiology. TRP expression patterns in non-neuronal cells with a focus on TRPA1, TRPC6, TRPM2, TRPM5, TRPM7, TRPV2, TRPV4 and TRPV6 channels are presented, and their roles in barrier function, immune regulation and phagocytosis are summarized. Moreover, TRP channels as future pharmacological targets in chronic obstructive pulmonary disease (COPD), asthma, cystic and pulmonary fibrosis as well as lung edema are discussed. [ABSTRACT FROM AUTHOR]

Intracellular Ca2+ signals are key for the regulation of cellular processes ranging from myocyte contraction, hormonal secretion, neural transmission, cellular metabolism, transcriptional regulation, and cell proliferation. Measurement of cellular Ca2+ is routinely performed using fluorescence microscopy with biological indicators. Analysis of deterministic signals is reasonably straightforward as relevant data can be discriminated based on the timing of cellular responses. However, analysis of stochastic, slower oscillatory events, as well as rapid subcellular Ca2+ responses, takes considerable time and effort which often includes visual analysis by trained investigators, especially when studying signals arising from cells embedded in complex tissues. The purpose of the current study was to determine if full-frame time-series and line-scan image analysis workflow of Fluo-4 generated Ca2+ fluorescence data from vascular myocytes could be automated without introducing errors. This evaluation was addressed by re-analyzing a published “gold standard” full-frame time-series dataset through visual analysis of Ca2+ signals from recordings made in pulmonary arterial myocytes of en face arterial preparations. We applied a combination of data driven and statistical approaches with comparisons to our published data to assess the fidelity of the various approaches. Regions of interest with Ca2+ oscillations were detected automatically post hoc using the LCPro plug-in for ImageJ. Oscillatory signals were separated based on event durations between 4 and 40 s. These data were filtered based on cutoffs obtained from multiple methods and compared to the published manually curated “gold standard” dataset. Subcellular focal and rapid Ca2+ “spark” events from line-scan recordings were examined using SparkLab 5.8, which is a custom automated detection and analysis program. After filtering, the number of true positives, false positives, and false negatives were calculated through comparisons to visually derived “gold standard” datasets. Positive predictive value, sensitivity, and false discovery rates were calculated. There were very few significant differences between the automated and manually curated results with respect to quality of the oscillatory and Ca2+ spark events, and there were no systematic biases in the data curation or filtering techniques. The lack of statistical difference in event quality between manual data curation and statistically derived critical cutoff techniques leads us to believe that automated analysis techniques can be reliably used to analyze spatial and temporal aspects to Ca2+ imaging data, which will improve experiment workflow.

Transmembrane protein 100 (TMEM100) is a crucial factor in the development and maintenance of the vascular system. The protein is involved in several processes such as angiogenesis, vascular morphogenesis, and integrity. Furthermore, TMEM100 is a downstream target of the BMP9/10 and BMPR2/ALK1 signaling pathways, which are key regulators of vascular development. Our recent studies have shown that TMEM100 is a lung endothelium enriched gene and plays a significant role in lung vascular repair and regeneration. The importance of TMEM100 in endothelial cells’ regeneration was demonstrated when Tmem100 was specifically deleted in endothelial cells, causing an impairment in their regenerative ability. However, the role of TMEM100 in various conditions and diseases is still largely unknown, making it an interesting area of research. This review summarizes the current knowledge of TMEM100, including its expression pattern, function, molecular signaling, and clinical implications, which could be valuable in the development of novel therapies for the treatment of cardiovascular and pulmonary diseases.

Background: Increasing iron bioavailability attenuates hypoxic pulmonary vasoconstriction in both lowlanders and Sherpas at high altitude. In contrast, the pulmonary vasculature of Andean individuals with chronic mountain sickness (CMS) is resistant to iron administration. Although pulmonary vascular remodeling and hypertension are characteristic features of CMS, the effect of iron administration in healthy Andean individuals, to our knowledge, has not been investigated. If the interplay between iron status and pulmonary vascular tone in healthy Andean individuals remains intact, this could provide valuable clinical insight into the role of iron regulation at high altitude.Research Question: Is the pulmonary vasculature in healthy Andean individuals responsive to iron infusion?Study Design and Methods: In a double-blinded, block-randomized design, 24 healthy high-altitude Andean individuals and 22 partially acclimatized lowlanders at 4,300 m (Cerro de Pasco, Peru) received an IV infusion of either 200 mg of iron (III)-hydroxide sucrose or saline. Markers of iron status were collected at baseline and 4 h after infusion. Echocardiography was performed in participants during room air breathing (partial pressure of inspired oxygen [Pio2] of approximately 96 mm Hg) and during exaggerated hypoxia (Pio2 of approximately 73 mm Hg) at baseline and at 2 and 4 h after the infusion.Results: Iron infusion reduced pulmonary artery systolic pressure (PASP) by approximately 2.5 mm Hg in room air (main effect, P < .001) and by approximately 7 mm Hg during exaggerated hypoxia (main effect, P < .001) in both lowlanders and healthy Andean highlanders. There was no change in PASP after the infusion of saline. Iron metrics were comparable between groups, except for serum ferritin, which was 1.8-fold higher at baseline in the Andean individuals than in the lowlanders (95% CI, 74-121 ng/mL vs 37-70 ng/mL, respectively; P = .003).Interpretation: The pulmonary vasculature of healthy Andean individuals and lowlanders remains sensitive to iron infusion, and this response seems to differ from the pathologic characteristics of CMS. [ABSTRACT FROM AUTHOR]

Purpose: Previous work suggests that endurance-trained athletes have superior pulmonary vasculature function as compared to untrained individuals, which may contribute to their greater maximal oxygen uptake ( V ˙ O2max). Inhaled nitric oxide (iNO) reduces pulmonary vascular resistance in healthy individuals, which could translate into greater cardiac output and improved V ˙ O2max, particularly in untrained individuals. The purpose of the study was to examine whether iNO improved V ˙ O2max in endurance trained and untrained individuals. Methods: Sixteen endurance-trained and sixteen untrained individuals with normal lung function completed this randomized double-blind cross-over study over four sessions. Experimental cardiopulmonary exercise tests were completed while breathing either normoxia (placebo) or 40 ppm of iNO, on separate days (order randomized). On an additional day, echocardiography was used to determine pulmonary artery systolic pressure at rest and during sub-maximal exercise (60 Watts) while participants breathed normoxia or iNO. Results: Right ventricular systolic pressure was significantly reduced by iNO during exercise (Placebo: 34 ± 7 vs. iNO: 32 ± 7; p = 0.04). V ˙ O2max was greater in the endurance trained group (Untrained: 3.1 ± 0.7 vs. Endurance: 4.3 ± 0.9 L min−1; p < 0.01), however, there was no effect of condition (p = 0.79) and no group by condition interaction (p = 0.68). Peak cardiac output was also unchanged by iNO in either group. Conclusion: Despite a reduction in right ventricular systolic pressure, the lack of change in V ˙ O2max with iNO suggests that the pulmonary vasculature does not limit V ˙ O2max in young healthy individuals, regardless of fitness level. [ABSTRACT FROM AUTHOR]

Imaging plays a central role in the diagnosis and management of all forms of pulmonary hypertension (PH). Although Doppler echocardiography is essential for the evaluation of PH, its ability to optimally evaluate the right ventricle and pulmonary vasculature is limited by its 2-dimensional planar capabilities. Magnetic resonance and computed tomography are capable of determining the etiology and pathophysiology of PH, and can be very useful in the management of these patients. Exciting new techniques such as right ventricle tissue characterization with T1 mapping, 4-dimensional flow of the right ventricle and pulmonary arteries, and computed tomography lung perfusion imaging are paving the way for a new era of imaging in PH. These imaging modalities complement echocardiography and invasive hemodynamic testing and may be useful as surrogate endpoints for early phase PH clinical trials. Here we discuss the role of magnetic resonance imaging and computed tomography in the diagnosis and management of PH, including current uses and novel research applications, and we discuss the role of value-based imaging in PH.

Abstract Background Patients with Congenital heart disease (CHD) require repetitive imaging of the pulmonary vasculature throughout their life. In this study, we compared a novel Compressed SENSE accelerated (factor 9) electrocardiogram (ECG)- and respiratory-triggered 3D modified Relaxation-Enhanced Angiography without Contrast and Triggering (modified REACT-non-contrast-enhanced magnetic resonance angiography (modified REACT-non-CE-MRA)) with standard non-ECG-triggered time-resolved 4D CE-MRA for imaging of the pulmonary arteries and veins in patients with CHD. Methods This retrospective analysis of 25 patients (June 2018–April 2019) with known or suspected CHD was independently conducted by two radiologists executing measurements on modified REACT-non-CE-MRA and 4D CE-MRA on seven dedicated points (inner edge): Main pulmonary artery (MPA), right and left pulmonary artery, right superior and inferior pulmonary vein, left superior (LSPV) and inferior pulmonary vein. Image quality for arteries and veins was evaluated on a four-point scale in consensus. Results Twenty-three of the 25 included patients presented a CHD. There was a high interobserver agreement for both methods of imaging at the pulmonary arteries (ICC ≥ 0.96); at the pulmonary veins, modified REACT-non-CE-MRA showed a slightly higher agreement, pronounced at LSPV (ICC 0.946 vs. 0.895). Measurements in 4D CE-MRA showed higher diameter values compared to modified REACT-non-CE-MRA, at the pulmonary arteries reaching significant difference (e.g. MPA: mean 0.408 mm, p = 0.002). Modified REACT-non-CE-MRA (average acquisition time 07:01 ± 02:44 min) showed significant better image quality than 4D CE-MRA at the pulmonary arteries (3.84 vs. 3.32, p

The development of an in vitro system for the study of lung vascular disease is critical to understanding human pathologies. Conventional culture systems fail to fully recapitulate native microenvironmental conditions and are typically limited in their ability to represent human pathophysiology for the study of disease and drug mechanisms. Whole organ decellularization provides a means to developing a construct that recapitulates structural, mechanical, and biological features of a complete vascular structure. Here, we developed a culture protocol to improve endothelial cell coverage in whole lung scaffolds and used single-cell RNA-sequencing analysis to explore the impact of decellularized whole lung scaffolds on endothelial phenotypes and functions in a biomimetic bioreactor system. Intriguingly, we found that the phenotype and functional signals of primary pulmonary microvascular revert back—at least partially—toward native lung endothelium. Additionally, human induced pluripotent stem cell-derived endothelium cultured in decellularized lung systems start to gain various native human endothelial phenotypes. Vascular barrier function was partially restored, while small capillaries remained patent in endothelial cell-repopulated lungs. To evaluate the ability of the engineered endothelium to modulate permeability in response to exogenous stimuli, lipopolysaccharide (LPS) was introduced into repopulated lungs to simulate acute lung injury. After LPS treatment, proinflammatory signals were significantly increased and the vascular barrier was impaired. Taken together, these results demonstrate a novel platform that recapitulates some pulmonary microvascular functions and phenotypes at a whole organ level. This development may help pave the way for using the whole organ engineering approach to model vascular diseases.

Background: Endoscopic staplers are common surgical devices used for the ligation and division of vasculature in thoracic procedures. When a stapler ligates and divides pulmonary vasculature, potentially catastrophic intraoperative bleeding at the staple-line may occur. The aim of this study was to confirm the safety and discuss the utility of a two-row stapler reload, by assessing the incidence of clinically necessary intraoperative hemostatic intervention when applied to pulmonary vasculature in real-world applications., Methods: This study was designed as a prospective non-comparative registry study conducted in seven centers across the United States, to confirm the safety and performance of Signia™ Small Diameter Reloads (SDR) when used for indicated thoracic surgical procedures. The primary endpoint was the incidence of hemostatic intervention related to the ligation and division of pulmonary arteries and veins. A five-point Likert scale scored hemostasis of each SDR staple-line. Secondary endpoints included the incidence of device-related only adverse events (AEs), device deficiencies, and procedure-related hospital readmission up to and including 30 days post operation., Results: SDR was fired 302 times across pulmonary vasculature in 120 subjects. Three firings required clinically necessary hemostatic intervention for an intervention rate of 0.99% (3 of 302 firings). Moreover, 97.5% (117 of 120 subjects) had intact SDR staple-lines regardless of surgical access or stapler handle preference. Only 4 (3.3%) thoracoscopic and robotic procedures converted to open, but none were due to SDR staple-lines. There was no statistically significant difference between the Likert score of transected arteries compared to veins (P=0.61). There were no device deficiencies or device-only related AEs reported., Conclusions: In this study, the two-row stapler reloads demonstrated favorable safety and efficacy profiles when fired across hilar vessels in the thoracic space with a 99% hemostatic rate, independent of surgical access and stapler handle preference., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-179/coif). All the authors report that the study was sponsored and funded by Medtronic, which contributed to the study design, data collection analysis, and manuscript writing. S.J.K., D.D.S., C.W.S. and P.G.S. are investigators in the Medtronic-sponsored Signia™ Small Diameter Reload Registry study and their institutions have received funds for participation. S.J.K. is a consultant of Medtronic. D.D.S. is an educational consultant of Covidien. N.P.D. and S.A. are current full-time employees of Medtronic and have stock options through Employee Stock Purchase Plan (ESPP). The authors have no other conflicts of interest to declare., (2024 Journal of Thoracic Disease. All rights reserved.)

The pulmonary vasculature consists of a large arterial and venous tree with a vast alveolar capillary network (ACN) in between. Both conducting blood vessels and the gas-exchanging capillaries are part of important human lung diseases, including bronchopulmonary dysplasia, pulmonary hypertension and chronic obstructive pulmonary disease. Morphological tools to investigate the different parts of the pulmonary vasculature quantitatively and in three dimensions are crucial for a better understanding of the contribution of the blood vessels to the pathophysiology and effects of lung diseases. In recent years, new stereological methods and imaging techniques have expanded the analytical tool box and therefore the conclusive power of morphological analyses of the pulmonary vasculature. Three of these developments are presented and discussed in this review article, namely (1) stereological quantification of the number of capillary loops, (2) serial block-face scanning electron microscopy of the ACN and (3) labeling of branching generations in light microscopic sections based on arterial tree segmentations of micro-computed tomography data sets of whole lungs. The implementation of these approaches in research work requires expertise in lung preparation, multimodal imaging at different scales, an advanced IT infrastructure and expertise in image analysis. However, they are expected to provide important data that cannot be obtained by previously existing methodology. [ABSTRACT FROM AUTHOR]

This study reports systematic longitudinal pathophysiology of lung parenchymal and vascular effects of asymptomatic COVID-19 pneumonia in a young, healthy never-smoking male. Inspiratory and expiratory noncontrast along with contrast dual-energy computed tomography (DECT) scans of the chest were performed at baseline on the day of acute COVID-19 diagnosis (day 0), and across a 90-day period. Despite normal vital signs and pulmonary function tests on the day of diagnosis, the CT scans and corresponding quantification metrics detected abnormalities in parenchymal expansion based on image registration, ground-glass (GGO) texture (inflammation) as well as DECT-derived pulmonary blood volume (PBV). Follow-up scans on day 30 showed improvement in the lung parenchymal mechanics as well as reduced GGO and improved PBV distribution. Improvements in lung PBV continued until day 90. However, the heterogeneity of parenchymal mechanics and texture-derived GGO increased on days 60 and 90. We highlight that even asymptomatic COVID-19 infection with unremarkable vital signs and pulmonary function tests can have measurable effects on lung parenchymal mechanics and vascular pathophysiology, which may follow apparently different clinical courses. For this asymptomatic subject, post COVID-19 regional mechanics demonstrated persistent increased heterogeneity concomitant with return of elevated GGOs, despite early improvements in vascular derangement. [ABSTRACT FROM AUTHOR]

This paper presents a three-dimensional finite element model for cyclic adenosine monophosphate (cAMP) signaling. Governing equations for the synthesis, diffusion, and degradation of cAMP were numerically implemented using the finite element method. Simulated results were displayed as time course plots of cAMP concentrations at selected nodes within the discretized geometry. The validity of the finite element model was assessed by comparing simulated results against analytical or other numerical solutions of cAMP concentration distribution for a spherical cellular volume. An endothelial cell was also simulated using its discretized geometry obtained from microscopic cellular cross-sectional images. Simulated solutions using the spherical cellular volume produced near identical cAMP concentration plots to the analytical solutions and were in good agreements with numerical results obtained from VCell, an existing software package for modeling cell biological systems. The validated 3-D finite element model was then employed to simulate the cAMP signaling pathway within a pulmonary microvascular endothelial cell geometry.

Pannexin 1 (Panx1), an ATP-efflux pathway, has been linked with inflammation in pulmonary capillaries. However, the physiological roles of endothelial Panx1 in the pulmonary vasculature are unknown. Endothelial transient receptor potential vanilloid 4 (TRPV4) channels lower pulmonary artery (PA) contractility and exogenous ATP activates endothelial TRPV4 channels. We hypothesized that endothelial Panx1–ATP–TRPV4 channel signaling promotes vasodilation and lowers pulmonary arterial pressure (PAP). Endothelial, but not smooth muscle, knockout of Panx1 increased PA contractility and raised PAP in mice. Flow/shear stress increased ATP efflux through endothelial Panx1 in PAs. Panx1-effluxed extracellular ATP signaled through purinergic P2Y2 receptor (P2Y2R) to activate protein kinase Cα (PKCα), which in turn activated endothelial TRPV4 channels. Finally, caveolin-1 provided a signaling scaffold for endothelial Panx1, P2Y2R, PKCα, and TRPV4 channels in PAs, promoting their spatial proximity and enabling signaling interactions. These results indicate that endothelial Panx1–P2Y2R–TRPV4 channel signaling, facilitated by caveolin-1, reduces PA contractility and lowers PAP in mice.

Our respiratory system is exposed to toxicants and pathogens from both sides: the airways and the vasculature. While tracheal, bronchial and alveolar epithelial cells form a natural barrier in the airways, endothelial cells protect the lung from perfused toxic compounds, particulate matter and invading microorganism in the vascular system. Damages induce inflammation by our immune response and wound healing by (myo)fibroblast proliferation. Members of the transient receptor potential (TRP) superfamily of ion channel are expressed in many cells of the respiratory tract and serve multiple functions in physiology and pathophysiology. TRP expression patterns in non-neuronal cells with a focus on TRPA1, TRPC6, TRPM2, TRPM5, TRPM7, TRPV2, TRPV4 and TRPV6 channels are presented, and their roles in barrier function, immune regulation and phagocytosis are summarized. Moreover, TRP channels as future pharmacological targets in chronic obstructive pulmonary disease (COPD), asthma, cystic and pulmonary fibrosis as well as lung edema are discussed.

Aberrant transforming growth factor-β (TGF-β) signaling activation is linked to pulmonary arterial hypertension (PAH). BMPR2 mutations perturb the balance between bone morphogenetic protein (BMP) and TGF-β pathways, leading to vascular remodeling, narrowing of the lumen of pulmonary vasculature, and clinical symptoms. This forum highlights the association of the TGF-β pathway with pathogenesis and therapeutic approaches. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Preclinical human-relevant modeling of organ-specific vasculature offers a unique opportunity to recreate pathophysiological intercellular, tissue-tissue, and cell-matrix interactions for a broad range of applications. Lung vasculature is particularly important due to its involvement in genesis and progression of rare, debilitating disorders as well as common chronic pathologies. Here, we provide an overview of the latest advances in the development of pulmonary vascular (PV) models using emerging microfluidic tissue engineering technology Organs-on-Chips (so-called PV-Chips). We first review the currently reported PV-Chip systems and their key features, and then critically discuss their major limitations in reproducing in vivo -seen and disease-relevant cellularity, localization, and microstructure. We conclude by presenting latest efforts to overcome such technical and biological limitations and future directions. [Display omitted] [ABSTRACT FROM AUTHOR]

Chronic thrombo-embolic pulmonary hypertension (CTEPH) develops in a subset of patients after acute pulmonary embolism. In CTEPH, pulmonary vascular resistance, which is initially elevated due to the obstructions in the larger pulmonary arteries, is further increased by pulmonary microvascular remodeling. The increased afterload of the right ventricle (RV) leads to RV dilation and hypertrophy. This RV remodeling predisposes to arrhythmogenesis and RV failure. Yet, mechanisms involved in pulmonary microvascular remodeling, processes underlying the RV structural and functional adaptability in CTEPH as well as determinants of the susceptibility to arrhythmias such as atrial fibrillation in the context of CTEPH remain incompletely understood. Several large animal models with critical clinical features of human CTEPH and subsequent RV remodeling have relatively recently been developed in swine, sheep, and dogs. In this review we will discuss the current knowledge on the processes underlying development and progression of CTEPH, and on how animal models can help enlarge understanding of these processes.

There are no FDA-approved drugs to mitigate the delayed effects of radiation exposure that may occur after a radiological attack or nuclear accident. To date, angiotensin-converting enzyme inhibitors are one of the most successful candidates for mitigation of hematopoietic, lung, kidney, and brain injuries in rodent models and may mitigate delayed radiation injuries after radiotherapy. Rat models of partial body irradiation sparing part of one hind leg (leg-out PBI) have been developed to simultaneously expose multiple organs to high doses of ionizing radiation and avoid lethal hematological toxicity to study the late effects of radiation. Exposures between 9 and 14 Gy damage the gut and bone marrow (acute radiation syndrome), followed by delayed injuries to the lung, heart, and kidney. The goal of the current study is to compare the pharmacokinetics (PK) of a lead angiotensin converting enzyme (ACE) inhibitor, lisinopril, in irradiated vs. nonirradiated rats, as a step toward licensure by the FDA.Methods: Female WAG/RijCmcr rats were irradiated with 12.5–13 Gy leg-out PBI. At day 35 after irradiation, during a latent period for injury, irradiated and nonirradiated siblings received a single gavage (0.3 mg, 0.6 mg) or intravenous injection (0.06 mg) of lisinopril. Plasma, urine, lung, liver and kidney levels of lisinopril were measured at different times. PK modeling (R package) was performed to track distribution of lisinopril in different compartments.Results: A two-compartment (central plasma and periphery) PK model best fit lisinopril measurements, with two additional components, the gavage and urine. The absorption and renal clearance rates were similar between nonirradiated and irradiated animals (respectively: ratios 0.883, p = 0.527; 0.943, p = 0.605). Inter-compartmental clearance (from plasma to periphery) for the irradiated rats was lower than for the nonirradiated rats (ratio 0.615, p = 0.003), while the bioavailability of the drug was 33% higher (ratio = 1.326, p < 0.001).Interpretation: Since receptors for lisinopril are present in endothelial cells lining blood vessels, and radiation induces vascular regression, it is possible that less lisinopril remains bound in irradiated rats, increasing circulating levels of the drug. However, this study cannot rule out changes in total amount of lisinopril absorbed or excreted long-term, after irradiation in rats.

• Hypoxia-induced mtROS differentially regulates pulmonary and systemic vascular remodeling. • Hypoxic PASMCs displayed apoptosis-resistant phenotype despite increased mtROS-induced DNA damage. • Conversely, modest mtROS levels triggered autophagy-mediated hASMC proliferation under hypoxia. Vascular remodeling plays a pivotal role in regulation of hypoxia-mediated pulmonary and systemic hypertension via the phenotypic modulation of smooth muscle cells (SMCs) of pulmonary and systemic arteries, respectively. Mitochondria serve as putative oxygen (O 2) sensors, and consequently, adaptations to hypoxia are mediated via HIF (hypoxia-inducible factors) activation, which impinges on mitochondrial function by suppressing the mitochondrial activity. Therefore, we explored the implication of hypoxia-mediated mitochondrial stress in pulmonary and systemic arterial remodeling. The hypoxic (10% O 2) effect on human pulmonary artery and aortic SMCs was examined in vitro by cell viability assay, proliferation index, autophagy, and comet assays. Mitochondrial ROS (mtROS), membrane potential (MMP), and mitochondrial morphology were assessed using mitochondrial-selective fluorescent probes. Further, the cell cycle distribution was analyzed by flow cytometry using propidium iodide staining. Our data indicate no significant alterations in cell viability and active proliferation of hypoxic PASMCs; however, an excessive rise in mtROS production and disrupted MMP, accompanied by enhanced DNA damage and reduced autophagy was observed, highlighting the 'apoptosis resistance' phenotype in these cells. Conversely, in hypoxia-treated hASMCs, a modest rise in mtROS levels was associated with reduced DNA damage; followed by upregulated autophagy; increased S–phase DNA content and cell viability, depicting the cytoprotective effect of hypoxia-induced autophagy against mitochondrial damage in hASMCs. Our findings suggest that differential impact of mtROS on proliferative capacity may contribute to the variable hypoxic responses in pulmonary and systemic vasculature. Therefore, targeting mtROS may serve as an effective therapeutic strategy to prevent hypoxia-induced hypertension. [ABSTRACT FROM AUTHOR]