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Various lung diseases, including pulmonary hypertension, chronic obstructive pulmonary disease or bronchopulmonary dysplasia, are associated with structural and architectural alterations of the pulmonary vasculature. The light microscopic (LM) analysis of the blood vessels is limited by the fact that it is impossible to identify which generation of the arterial tree an arterial profile within a LM microscopic section belongs to. Therefore, we established a workflow that allows for the generation-specific quantitative (stereological) analysis of pulmonary blood vessels. A whole left rabbit lung was fixed by vascular perfusion, embedded in glycol methacrylate and imaged by micro-computed tomography (µCT). The lung was then exhaustively sectioned and 20 consecutive sections were collected every 100 µm to obtain a systematic uniform random sample of the whole lung. The digital processing involved segmentation of the arterial tree, generation analysis, registration of LM sections with the µCT data as well as registration of the segmentation and the LM images. The present study demonstrates that it is feasible to identify arterial profiles according to their generation based on a generation-specific color code. Stereological analysis for the first three arterial generations of the monopodial branching of the vasculature included volume fraction, total volume, lumen-to-wall ratio and wall thickness for each arterial generation. In conclusion, the correlative image analysis of µCT and LM-based datasets is an innovative method to assess the pulmonary vasculature quantitatively. [ABSTRACT FROM AUTHOR]

In the pulmonary vasculature, mechanical forces such as cyclic stretch induce changes in vascular signaling, tone and remodeling. Nitric oxide is a potent regulator of soluble guanylate cyclase (sGC), which drives cGMP production, causing vasorelaxation. Pulmonary artery smooth muscle cells (PASMCs) express inducible nitric oxide synthase (iNOS), and while iNOS expression increases during late gestation, little is known about how cyclic stretch impacts this pathway. In this study, PASMC were subjected to cyclic stretch of 20% amplitude and frequency of 1 Hz for 24 h and compared to control cells maintained under static conditions. Cyclic stretch significantly increased cytosolic oxidative stress as compared to static cells (62.9 ± 5.9% vs. 33.3 ± 5.7% maximal oxidation), as measured by the intracellular redox sensor roGFP. Cyclic stretch also increased sGCβ protein expression (2.5 ± 0.9-fold), sGC activity (1.5 ± 0.2-fold) and cGMP levels (1.8 ± 0.2-fold), as well as iNOS mRNA and protein expression (3.0 ± 0.9 and 2.6 ± 0.7-fold, respectively) relative to control cells. An antioxidant, recombinant human superoxide dismutase (rhSOD), significantly decreased stretch-induced cytosolic oxidative stress, but did not block stretch-induced sGC activity. Inhibition of iNOS with 1400 W or an iNOS-specific siRNA inhibited stretch-induced sGC activity by 30% and 68% respectively vs. static controls. In conclusion, cyclic stretch increases sGC expression and activity in an iNOS-dependent manner in PASMC from fetal lambs. The mechanism that produces iNOS and sGC upregulation is not yet known, but we speculate these effects represent an early compensatory mechanism to counteract the effects of stretch-induced oxidative stress. A better understanding of the interplay between these two distinct pathways could provide key insights into future avenues to treat infants with pulmonary hypertension.

Pulmonary hypertension in the neonatal population can be acute or chronic and carries significant risk for morbidity and mortality. It can be idiopathic but more often is associated with comorbid pulmonary and heart disease. There are several pharmacotherapeutics aimed at pulmonary vasodilation. This review highlights the most common agents as well as those on the horizon for the treatment of pulmonary hypertension in the neonate., Competing Interests: Disclosure None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Fetal lungs have fewer and smaller arteries with higher pulmonary vascular resistance (PVR) than a newborn. As gestation advances, the pulmonary circulation becomes more sensitive to changes in pulmonary arterial oxygen tension, which prepares them for the dramatic drop in PVR and increase in pulmonary blood flow (PBF) that occur when the baby takes its first few breaths of air, thus driving the transition from fetal to postnatal circulation. Dynamic and intricate regulatory mechanisms control PBF throughout development and are essential in supporting gas exchange after birth. Understanding these concepts is crucial given the role the pulmonary vasculature plays in the development of complications with transition, such as in the setting of persistent pulmonary hypertension of the newborn and congenital heart disease. An improved understanding of pulmonary vascular regulation may reveal opportunities for better clinical management., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Individuals with single ventricle congenital heart disease (CHD) undergo multiple staged surgical palliations. Staged single ventricle palliation with a superior cavopulmonary connection (SCPC) in infancy followed by a Fontan in early childhood relies on passive, unobstructed pulmonary blood flow and normal pulmonary vasculature. We hypothesized that patients with echocardiographic identification of retrograde flow in a branch pulmonary artery (PA) after SCPC or Fontan are at increased risk for adverse outcomes. We conducted a retrospective chart review of patients seen at Children's Wisconsin from 1999 to 2019. Inclusion criteria included a history of single ventricle congenital heart disease and surgical palliation with a superior cavopulmonary connection (SCPC). We created two cohorts based on transthoracic echocardiographic identification of branch PA flow patterns: those with color Doppler-defined pulmonary artery flow reversal (PA reversal cohort) and those with normal anterograde flow (Non-reversal cohort). We identified 21 patients in the PA reversal cohort and 539 patients in the Non-reversal cohort. The PA reversal cohort had increased hospital length of stay after SCPC palliation (p < 0.001) and decreased transplant-free survival (p = 0.032), but there was no difference in overall survival (p = 0.099). There was no difference in hospital length of stay after Fontan (p = 0.17); however, the PA reversal cohort was significantly less likely to progress to Fontan palliation during early childhood (p = 0.005). Echocardiographic color Doppler identification of branch PA flow reversal in patients with single ventricle physiology is a high-risk indicator for adverse short- and long-term outcomes. [ABSTRACT FROM AUTHOR]

Microvesicles (MVs), a plasma membrane-derived subclass of extracellular vesicles, are produced and released into the circulation during systemic inflammation, yet little is known of cell/tissue-specific uptake of MVs under these conditions. We hypothesized that monocytes contribute to uptake of circulating MVs and that their increased margination to the pulmonary circulation and functional priming during systemic inflammation produces substantive changes to the systemic MV homing profile. Cellular uptake of i.v.-injected, fluorescently labelled MVs (J774.1 macrophage-derived) in vivo was quantified by flow cytometry in vascular cell populations of the lungs, liver and spleen of C57BL6 mice. Under normal conditions, both Ly6Chigh and Ly6Clow monocytes contributed to MV uptake but liver Kupffer cells were the dominant target cell population. Following induction of sub-clinical endotoxemia with low-dose i.v. LPS, MV uptake by lung-marginated Ly6Chigh monocytes increased markedly, both at the individual cell level (~2.5-fold) and through substantive expansion of their numbers (~8-fold), whereas uptake by splenic macrophages was unchanged and uptake by Kupffer cells actually decreased (~50%). Further analysis of MV uptake within the pulmonary vasculature using a combined model approach of in vivo macrophage depletion, ex vivo isolated perfused lungs and in vitro lung perfusate cell-based assays, indicated that Ly6Chigh monocytes possess a high MV uptake capacity (equivalent to Kupffer cells), that is enhanced directly by endotoxemia and ablated in the presence of phosphatidylserine (PS)-enriched liposomes and β3 integrin receptor blocking peptide. Accordingly, i.v.-injected PS-enriched liposomes underwent a redistribution of cellular uptake during endotoxemia similar to MVs, with enhanced uptake by Ly6Chigh monocytes and reduced uptake by Kupffer cells. These findings indicate that monocytes, particularly lung-marginated Ly6Chigh subset monocytes, become a dominant target cell population for MVs during systemic inflammation, with significant implications for the function and targeting of endogenous and therapeutically administered MVs, lending novel insights into the pathophysiology of pulmonary vascular inflammation. [ABSTRACT FROM AUTHOR]

In the healthy, untrained young adult, a case is made for a respiratory system (airways, pulmonary vasculature, lung parenchyma, respiratory muscles, and neural ventilatory control system) that is near ideally designed to ensure a highly efficient, homeostatic response to exercise of varying intensities and durations. Our aim was then to consider circumstances in which the intra/extrathoracic airways, pulmonary vasculature, respiratory muscles, and/or blood-gas distribution are underbuilt or inadequately regulated relative to the demands imposed by the cardiovascular system. In these instances, the respiratory system presents a significant limitation to O2 transport and contributes to the occurrence of locomotor muscle fatigue, inhibition of central locomotor output, and exercise performance. Most prominent in these examples of an "underbuilt" respiratory system are highly trained endurance athletes, with additional influences of sex, aging, hypoxic environments, and the highly inbred equine. We summarize by evaluating the relative influences of these respiratory system limitations on exercise performance and their impact on pathophysiology and provide recommendations for future investigation. [ABSTRACT FROM AUTHOR]

Background Although most newly presenting patients with pulmonary hypertension (PH) have elevated pulmonary artery wedge pressure, identification of so‐called postcapillary PH can be challenging. A noninvasive tool predicting elevated pulmonary artery wedge pressure in patients with incident PH may help avoid unnecessary invasive diagnostic procedures. Methods and Results A combination of clinical data, ECG, and echocardiographic parameters was used to refine a previously developed left heart failure risk score in a retrospective cohort of pre‐ and postcapillary PH patients. This updated score (renamed the OPTICS risk score) was externally validated in a prospective cohort of patients from 12 Dutch nonreferral centers the OPTICS network. Using the updated OPTICS risk score, the presence of postcapillary PH could be predicted on the basis of body mass index ≥30, diabetes mellitus, atrial fibrillation, dyslipidemia, history of valvular surgery, sum of SV1 (deflection in V1 in millimeters) and RV6 (deflection in V6 in millimeters) on ECG, and left atrial dilation. The external validation cohort included 81 postcapillary PH patients and 66 precapillary PH patients. Using a predefined cutoff of >104, the OPTICS score had 100% specificity for postcapillary PH (sensitivity, 22%). In addition, we investigated whether a high probability of heart failure with preserved ejection fraction, assessed by the H2FPEF score (obesity, atrial fibrillation, age >60 yrs, ≥2 antihypertensives, E/e' >9, and pulmonary artery systolic pressure by echo >35 mmHg), similarly predicted the presence of elevated pulmonary artery wedge pressure. High probability of heart failure with preserved ejection fraction (H2FPEF score ≥6) was less specific for postcapillary PH. Conclusions In a community setting, the OPTICS risk score can predict elevated pulmonary artery wedge pressure in PH patients without clear signs of left‐sided heart disease. The OPTICS risk score may be used to tailor the decision to perform invasive diagnostic testing.

Microvesicles (MVs), a plasma membrane-derived subclass of extracellular vesicles, are produced and released into the circulation during systemic inflammation, yet little is known of cell/tissue-specific uptake of MVs under these conditions. We hypothesized that monocytes contribute to uptake of circulating MVs and that their increased margination to the pulmonary circulation and functional priming during systemic inflammation produces substantive changes to the systemic MV homing profile. Cellular uptake of i.v.-injected, fluorescently labelled MVs (J774.1 macrophage-derived) in vivo was quantified by flow cytometry in vascular cell populations of the lungs, liver and spleen of C57BL6 mice. Under normal conditions, both Ly6Chigh and Ly6Clow monocytes contributed to MV uptake but liver Kupffer cells were the dominant target cell population. Following induction of sub-clinical endotoxemia with low-dose i.v. LPS, MV uptake by lung-marginated Ly6Chigh monocytes increased markedly, both at the individual cell level (~2.5-fold) and through substantive expansion of their numbers (~8-fold), whereas uptake by splenic macrophages was unchanged and uptake by Kupffer cells actually decreased (~50%). Further analysis of MV uptake within the pulmonary vasculature using a combined model approach of in vivo macrophage depletion, ex vivo isolated perfused lungs and in vitro lung perfusate cell-based assays, indicated that Ly6Chigh monocytes possess a high MV uptake capacity (equivalent to Kupffer cells), that is enhanced directly by endotoxemia and ablated in the presence of phosphatidylserine (PS)-enriched liposomes and β3 integrin receptor blocking peptide. Accordingly, i.v.-injected PS-enriched liposomes underwent a redistribution of cellular uptake during endotoxemia similar to MVs, with enhanced uptake by Ly6Chigh monocytes and reduced uptake by Kupffer cells. These findings indicate that monocytes, particularly lung-marginated Ly6Chigh subset monocytes, become a dominant target cell population for MVs during systemic inflammation, with significant implications for the function and targeting of endogenous and therapeutically administered MVs, lending novel insights into the pathophysiology of pulmonary vascular inflammation.

K+ channels play a fundamental role regulating membrane potential of pulmonary artery (PA) smooth muscle cells and their impairment is a common feature in pulmonary arterial hypertension (PAH). K+ voltage-gated channel subfamily Q (KCNQ1-5) or Kv7 channels and their regulatory subunits subfamily E (KCNE) regulatory subunits are known to regulate vascular tone, but whether Kv7 channel function is impaired in PAH and how this can affect the rationale for targeting Kv7 channels in PAH remains unknown. Here, we have studied the role of Kv7/KCNE subunits in rat PA and their possible alteration in PAH. Using the patch-clamp technique, we found that the total K+ current is reduced in PA smooth muscle cells from pulmonary hypertension animals (SU5416 plus hypoxia) and Kv7 currents made a higher contribution to the net K+ current. Likewise, enhanced vascular responses to Kv7 channel modulators were found in pulmonary hypertension rats. Accordingly, KCNE4 subunit was highly upregulated in lungs from pulmonary hypertension animals and patients. Additionally, Kv7 channel activity was enhanced in the presence of Kv1.5 and TASK-1 channel inhibitors and this was associated with an increased KCNE4 membrane abundance. Compared with systemic arteries, PA showed a poor response to Kv7 channel modulators which was associated with reduced expression and membrane abundance of Kv7.4 and KCNE4. Our data indicate that Kv7 channel function is preserved and KCNE4 is upregulated in PAH. Therefore, compared with other downregulated channels, the contribution of Kv7 channels is increased in PAH resulting in an enhanced sensitivity to Kv7 channel modulators. This study provides insight into the potential usefulness of targeting Kv7 channels in PAH. [ABSTRACT FROM AUTHOR]

The Fontan operation remains the final palliation for thousands of patients with complex congenital heart disease. By creating a Fontan circuit, control of cardiac output and congestion is wrested away from the ventricle and new haemodynamic forces take control. Understanding how to control the flow in the Fontan circuit will enable clinicians to improve patient management and possibly prevent future complications. CONCLUSION: This review proposes a framework of principles to conceptualise the functionality and limitations of a Fontan circulation. [ABSTRACT FROM AUTHOR]

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 < 0.001) and veins (3.32 vs. 2.72, p = 0.015). Conclusions: Compressed SENSE accelerated (factor 9) ECG- and respiratory-triggered 3D modified REACT-non-CE-MRA allows for reliable and fast imaging of the pulmonary arteries and veins with higher image quality and slightly higher interobserver agreement than 4D CE-MRA without contrast agent and associated disadvantages. Therefore, it represents a clinically suitable technique for patients requiring repetitive imaging of the pulmonary vasculature, e.g. patients with CHD. [ABSTRACT FROM AUTHOR]

In the lung, chronic alcohol consumption is a risk factor for acute respiratory distress syndrome (ARDS), a disorder that can be fatal due to airspace flooding. The severity of pulmonary edema is controlled by multiple barriers, and in particular the alveolar epithelial barrier and pulmonary microvasculature. However, to date, the effects of chronic alcohol ingestion on both of these barriers in the lung has not been directly and simultaneously measured. In addition the effects of alcohol on systemic, indirect lung injury versus direct injury have not been compared. In this study, we used tissue morphometry and Evans Blue permeability assays to assess the effects of alcohol and endotoxemia injury on pulmonary barrier function comparing intraperitoneal (IP) administration of lipopolysaccharide (LPS) to intratracheal (IT) administration. Consistent with previous reports, we found that in alcohol-fed mice, the alveolar barrier was impaired, allowing Evans Blue to permeate into the airspaces. Moreover, IT administered LPS caused a significant breach of both the alveolar epithelial and vascular barriers in alcohol-fed mice, whereas the endothelial barrier was less affected in response to IP administered LPS. The alveolar barrier of control mice remained intact for both IP and IT administered LPS. However, both injuries caused significant interstitial edema, independently of whether the mice were fed alcohol or not. These data suggest that in order to properly target pulmonary edema due to alcoholic lung syndrome, both the alveolar and endothelial barriers need to be considered as well as the nature of the "second hit" that initiates ARDS. [ABSTRACT FROM AUTHOR]

Abstract Background Plasma concentrations of endocan, a proteoglycan preferentially expressed in the pulmonary vasculature, may represent a biomarker of lung (dys)function. We sought to determine whether the measurement of plasma endocan levels early in the course of acute respiratory distress syndrome (ARDS) could help predict risk of death or of prolonged ventilation. Methods All patients present in the department of intensive care during a 150-day period were screened for ARDS (using the Berlin definition). Endocan concentrations were measured at the moment of ARDS diagnosis (T0) and the following morning (T1). We compared data from survivors and non-survivors and data from survivors with less than 10 days of ventilator support (good evolution) and those who died or needed more than 10 days of mechanical ventilation (poor evolution). Results are presented as numbers (percentages), mean ± standard deviation or medians (percentile 25–75). Results Ninety-six consecutive patients were included [median APACHE II score of 21 (17–27) and SOFA score of 9 (6–12), PaO2/FiO2 ratio 155 (113–206)]; 64 (67%) had sepsis and 51 (53%) were receiving norepinephrine. Non-survivors were older (66 ± 15 vs. 59 ± 18 years, p = 0.045) and had higher APACHE II scores [27 (22–30) vs. 20 (15–24), p

Pulmonary hypertension (PH) is defined as resting mean pulmonary artery pressure ≥25 mmHg measured by right heart catheterization. PH is a progressive, life-threatening disease with a variety of etiologies. Swift and accurate diagnosis of PH and appropriate classification in etiologic group will allow for earlier treatment and improved outcomes. A number of imaging tools are utilized in the evaluation of PH, such as chest X-ray, computed tomography (CT), ventilation/perfusion (V/Q) scan, and cardiac magnetic resonance imaging. Newer imaging tools such as dual-energy CT and single-photon emission computed tomography/computed tomography V/Q scanning have also emerged; however, their place in the diagnostic evaluation of PH remains to be determined. In general, each imaging technique provides incremental information, with varying degrees of sensitivity and specificity, which helps suspect the presence and identify the etiology of PH. The present study aims to provide a comprehensive review of the utility, advantages, and shortcomings of the imaging modalities that may be used to evaluate patients with PH.

FOXF1 heterozygous point mutations and genomic deletions have been reported in newborns with the neonatally lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). However, no gain-of-function mutations in FOXF1 have been identified yet in any human disease conditions. To study the effects of FOXF1 overexpression in lung development, we generated a Foxf1 overexpression mouse model by knocking-in a Cre-inducible Foxf1 allele into the ROSA26 (R26) locus. The mice were phenotyped using micro-computed tomography (micro-CT), head-out plethysmography, ChIP-seq and transcriptome analyses, immunohistochemistry, and lung histopathology. Thirty-five percent of heterozygous R26-Lox-Stop-Lox (LSL)-Foxf1 embryonic day (E)15.5 embryos exhibit subcutaneous edema, hemorrhages and die perinatally when bred to Tie2-cre mice, which targets Foxf1 overexpression to endothelial and hematopoietic cells. Histopathological and micro-CT evaluations revealed that R26Foxf1; Tie2-cre embryos have immature lungs with a diminished vascular network. Neonates exhibited respiratory deficits verified by detailed plethysmography studies. ChIP-seq and transcriptome analyses in E18.5 lungs identified Sox11, Ghr, Ednrb, and Slit2 as potential downstream targets of FOXF1. Our study shows that overexpression of the highly dosage-sensitive Foxf1 impairs lung development and causes vascular abnormalities. This has important clinical implications when considering potential gene therapy approaches to treat disorders of FOXF1 abnormal dosage, such as ACDMPV.

Cardiovascular imaging is essential in the evaluation and management of patients with pulmonary hypertension. Echocardiography and magnetic resonance imaging, in particular, provide basic measurements of pulmonary pressure and right ventricular function, but current technology allows for a much more comprehensive assessment. Many of these advancements have the potential to enhance risk stratification and provide additional phenotypic data that may strengthen or alter the therapeutic approach. This review will highlight multiple novel techniques from various imaging modalities and how this information can be applied in clinical practice. [ABSTRACT FROM AUTHOR]

Key points: Approximately 5–10% pregnancies are affected by fetal growth restriction.Preterm infants affected by fetal growth restriction have a higher incidence of bronchopulmonary dysplasia.The present study is the first to measure pulmonary artery thickness and stiffness.The findings show that impaired vasculogenesis may be a contributory factor in the higher incidence of bronchopulmonary dysplasia in preterm growth restricted infants.The study addresses the mechanistic link between fetal programming and vascular architecture and mechanics. Bronchopulmonary dysplasia is the most common respiratory sequelae of prematurity and histopathologically features fewer, dysmorphic pulmonary arteries. The present study aimed to characterize pulmonary artery mechanics and cardiac function in preterm infants with fetal growth restriction (FGR) compared to those appropriate for gestational age (AGA) in the early neonatal period. This prospective study reviewed 40 preterm infants between 28 to 32 weeks gestational age (GA). Twenty infants had a birthweight <10th centile and were compared with 20 preterm AGA infants. A single high resolution echocardiogram was performed to measure right pulmonary arterial and right ventricular (RV) indices. The GA and birthweight of FGR and AGA infants were 29.8 ± 1.3 vs. 30 ± 0.9 weeks (P = 0.78) and 923.4 g ± 168 vs. 1403 g ± 237 (P < 0.001), respectively. Assessments were made at 10.5 ± 1.3 days after birth. The FGR infants had significantly thicker right pulmonary artery inferior wall (843.5 ± 68 vs. 761 ± 40 μm, P < 0.001) with reduced pulsatility (51.6 ± 7.6 μm vs. 59.7 ± 7.5 μm, P = 0.001). The RV contractility [fractional area change (28.7 ± 3.8% vs 32.5 ± 3.1%, P = 0.001), tricuspid annular peak systolic excursion (TAPSE) (5.2 ± 0.3% vs. 5.9 ± 0.7%, P = 0.0002) and myocardial performance index (0.35 ± 0.03 vs. 0.28 ± 0.02, P < 0.001)] was significantly impaired in FGR infants. Significant correlation between RV longitudinal contractility (TAPSE) and time to peak velocity/RV ejection time (measure of RV afterload) was noted (r2 = 0.5, P < 0.001). Altered pulmonary vascular mechanics and cardiac performance reflect maladaptive changes in response to utero‐placental insufficiency. Whether managing pulmonary vascular disease will alter clinical outcomes remains to be studied prospectively. Key points: Approximately 5–10% pregnancies are affected by fetal growth restriction.Preterm infants affected by fetal growth restriction have a higher incidence of bronchopulmonary dysplasia.The present study is the first to measure pulmonary artery thickness and stiffness.The findings show that impaired vasculogenesis may be a contributory factor in the higher incidence of bronchopulmonary dysplasia in preterm growth restricted infants.The study addresses the mechanistic link between fetal programming and vascular architecture and mechanics. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) encompasses a group of progressive and incurable cardiopulmonary disorders characterized by pulmonary vascular remodeling and increased mean pulmonary artery pressure leading to right heart failure. Emerging data suggest a common etiology for the reported diverse molecular and physiological abnormalities observed in the pulmonary vasculature: the metabolic theory of PH. This theory proposes that aberrations in metabolism and mitochondrial function are a major underlying cause for the cellular and organ level PH phenotype. Additionally, the metabolic theory of PH provides a rationale for the observed metabolic defects in other organs and systems outside of the pulmonary vasculature, including the right ventricle (RV), immune system, and skeletal muscle. However, whether these metabolic changes are driving disease and the timing and extent of these aberrations are still unknown. This review highlights: 1) key examples of metabolic alterations in the pulmonary vasculature, RV, inflammatory cells, and skeletal muscle; 2) examples of promising therapeutic interventions directly modifying metabolism; and 3) key remaining questions about the role of metabolic remodeling in PH. [ABSTRACT FROM AUTHOR]

An increasing number of people are living or working at high altitudes (hypobaric hypoxia) and therefore suffering several physiological, biochemical, and molecular changes. Pulmonary vasculature is one of the main and first responses to hypoxia. These responses imply hypoxic pulmonary vasoconstriction (HPV), remodeling, and eventually pulmonary hypertension (PH). These events occur according to the type and extension of the exposure. There is also increasing evidence that these changes in the pulmonary vascular bed could be mainly attributed to a homeostatic imbalance as a result of increased levels of reactive oxygen species (ROS). The increase in ROS production during hypobaric hypoxia has been attributed to an enhanced activity and expression of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), though there is some dispute about which subunit is involved. This enzymatic complex may be directly induced by hypoxia-inducible factor-1α (HIF-1α). ROS has been found to be related to several pathways, cells, enzymes, and molecules in hypoxic pulmonary vasculature responses, from HPV to inflammation, and structural changes, such as remodeling and, ultimately, PH. Therefore, we performed a comprehensive review of the current evidence on the role of ROS in the development of pulmonary vasculature changes under hypoxic conditions, with a focus on hypobaric hypoxia. This review provides information supporting the role of oxidative stress (mainly ROS) in the pulmonary vasculature’s responses under hypobaric hypoxia and depicting possible future therapeutics or research targets. NADPH oxidase-produced oxidative stress is highlighted as a major source of ROS. Moreover, new molecules, such as asymmetric dimethylarginine, and critical inflammatory cells as fibroblasts, could be also involved. Several controversies remain regarding the role of ROS and the mechanisms involved in hypoxic responses that need to be elucidated.

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Abstract: Aging is associated with pulmonary vascular remodeling and reduced distensibility. We investigated the influence of aging on changes in cardiac output (Q), mean pulmonary artery pressure (mPAP), and lung diffusing capacity in response to alterations in thoracic blood volume. The role of pulmonary smooth muscle tone was also interrogated via pulmonary vasodilation. Nine younger (27 ± 4 years) and nine older (71 ± 4 years) healthy adults reached steady‐state in a Supine (0°), Upright (+20°), or Head‐down (−20°) position in order to alter thoracic blood volume. In each position, echocardiography was performed to calculate mPAP and Q, and lung diffusing capacity for carbon monoxide (DLCO) and nitric oxide (DLNO) was assessed. Next, 100 mg sildenafil was administered to reduce pulmonary smooth muscle tone, after which the protocol was repeated. mPAP (P ≤ 0.029) and Q (P ≤ 0.032) were lower in the Upright versus Supine and Head‐down positions, and mPAP was reduced following sildenafil administration (P = 0.019), in older adults only. SV was lower in the Upright versus Supine and Head‐down positions in both younger (P ≤ 0.008) and older (P ≤ 0.003) adults. DLCO and DLNO were not greatly altered by position changes or sildenafil administration. However, the DLNO/DLCO ratio was lower in the Supine and/or Head‐down positions (P ≤ 0.05), but higher following sildenafil administration (P ≤ 0.007), in both younger and older adults. In conclusion, older adults experience greater cardiopulmonary alterations following thoracic blood volume changes, and pulmonary smooth muscle tone plays a role in resting mPAP in older adults only. Furthermore, mPAP is an important determinant of pulmonary capillary blood volume distribution (DLNO/DLCO), regardless of age. [ABSTRACT FROM AUTHOR]

Alterations of the pulmonary vasculature are an important feature of human lung diseases such as chronic obstructive pulmonary disease, pulmonary hypertension, and bronchopulmonary dysplasia. Experimental studies to investigate the pathogenesis or a therapeutic intervention in animal models of these diseases often require robust, meaningful, and efficient morphometric data that allow for appropriate statistical testing. The gold standard for obtaining such data is design-based stereology. However, certain morphological characteristics of the pulmonary vasculature make the implementation of stereological methods challenging. For example, the alveolar capillary network functions according to the sheet flow principle, thus making unbiased length estimations impossible and requiring other strategies to obtain mechanistic morphometric data. Another example is the location of pathological changes along the branches of the vascular tree. For developmental defects like in bronchopulmonary dysplasia or for pulmonary hypertension, it is important to know whether certain segments of the vascular tree are preferentially altered. This cannot be overcome by traditional stereological methods but requires the combination of a three-dimensional data set and stereology. The present review aims at highlighting the great potential while discussing the major challenges (such as time consumption and data volume) of this combined approach. We hope to raise interest in the potential of this approach and thus stimulate solutions to overcome the existing challenges. [ABSTRACT FROM AUTHOR]

An increasing number of people are living or working at high altitudes (hypobaric hypoxia) and therefore suffering several physiological, biochemical, and molecular changes. Pulmonary vasculature is one of the main and first responses to hypoxia. These responses imply hypoxic pulmonary vasoconstriction (HPV), remodeling, and eventually pulmonary hypertension (PH). These events occur according to the type and extension of the exposure. There is also increasing evidence that these changes in the pulmonary vascular bed could be mainly attributed to a homeostatic imbalance as a result of increased levels of reactive oxygen species (ROS). The increase in ROS production during hypobaric hypoxia has been attributed to an enhanced activity and expression of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), though there is some dispute about which subunit is involved. This enzymatic complex may be directly induced by hypoxia-inducible factor-1α (HIF-1α). ROS has been found to be related to several pathways, cells, enzymes, and molecules in hypoxic pulmonary vasculature responses, from HPV to inflammation, and structural changes, such as remodeling and, ultimately, PH. Therefore, we performed a comprehensive review of the current evidence on the role of ROS in the development of pulmonary vasculature changes under hypoxic conditions, with a focus on hypobaric hypoxia. This review provides information supporting the role of oxidative stress (mainly ROS) in the pulmonary vasculature’s responses under hypobaric hypoxia and depicting possible future therapeutics or research targets. NADPH oxidase-produced oxidative stress is highlighted as a major source of ROS. Moreover, new molecules, such as asymmetric dimethylarginine, and critical inflammatory cells as fibroblasts, could be also involved. Several controversies remain regarding the role of ROS and the mechanisms involved in hypoxic responses that need to be elucidated. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) is the most common type of cancer in women and the second cause of cancer-related mortality world-wide. The majority of BC-related deaths is due to metastasis. Bone, lung, brain and liver are the primary target sites of BC metastasis. The clinical implications and mechanisms underlying bone metastasis have been reviewed before. Given the fact that BC lung metastasis (BCLM) usually produces symptoms only after the lungs have been vastly occupied with metastatic tumor masses, it is of paramount importance for diagnostic and prognostic, as well as therapeutic purposes to comprehend the molecular and cellular mechanisms underlying BCLM. Here, we review current insights into the organ-specificity of BC metastasis, including the role of cancer stem cells in triggering BC spread, the traveling of tumor cells in the blood stream and their migration across endothelial barriers, their adaptation to the lung microenvironment and the initiation of metastatic colonization within the lung.Conclusions: Detailed understanding of the mechanisms underlying BCLM will shed a new light on the identification of novel molecular targets to impede daunting pulmonary metastases in patients with breast cancer. [ABSTRACT FROM AUTHOR]