scholarly journals Chemokine signaling axis between endothelial and myeloid cells regulates development of pulmonary hypertension associated with pulmonary fibrosis and hypoxia

2019 ◽  
Vol 317 (4) ◽  
pp. L434-L444 ◽  
Author(s):  
Aline C. Oliveira ◽  
Chunhua Fu ◽  
Yuanqing Lu ◽  
Mason A. Williams ◽  
Liya Pi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Pulmonary Vascular Disease ◽  
Chronic Lung Diseases ◽  
Chemokine Signaling ◽  
Signaling Axis ◽  
Group 3

Pulmonary hypertension complicates the care of many patients with chronic lung diseases (defined as Group 3 pulmonary hypertension), yet the mechanisms that mediate the development of pulmonary vascular disease are not clearly defined. Despite being the most prevalent form of pulmonary hypertension, to date there is no approved treatment for patients with disease. Myeloid-derived suppressor cells (MDSCs) and endothelial cells in the lung express the chemokine receptor CXCR2, implicated in the evolution of both neoplastic and pulmonary vascular remodeling. However, precise cellular contribution to lung disease is unknown. Therefore, we used mice with tissue-specific deletion of CXCR2 to investigate the role of this receptor in Group 3 pulmonary hypertension. Deletion of CXCR2 in myeloid cells attenuated the recruitment of polymorphonuclear MDSCs to the lungs, inhibited vascular remodeling, and protected against pulmonary hypertension. Conversely, loss of CXCR2 in endothelial cells resulted in worsened vascular remodeling, associated with increased MDSC migratory capacity attributable to increased ligand availability, consistent with analyzed patient sample data. Taken together, these data suggest that CXCR2 regulates MDSC activation, informing potential therapeutic application of MDSC-targeted treatments.

Abstract 19126: Endothelial-specific Deletion of Prolyl Hydroxylase Domain Protein 2 (PHD2) Results in Severe Pulmonary Hypertension in Mice by Enhancing the HIF2alpha Signaling Pathway

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Haiyang Tang ◽  
Yali Gu ◽  
Ramon Aryon ◽  
Shanshan Song ◽  
Ruby A Fernandez ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Remodeling ◽  
Normoxic Condition ◽  
Severe Pulmonary Hypertension ◽  
Pulmonary Arterial ◽  
Domain Protein ◽  
Specific Deletion

Rationale: Sustained pulmonary vasoconstriction and excessive vascular remodeling are major causes of elevated pulmonary vascular resistance which leads to increased pulmonary arterial pressure in patients with pulmonary hypertension. Hypoxic-inducible factor (HIF) and its upstream regulators have been linked to the hypoxia response in vascular remodeling and the development of pulmonary hypertension. In this study, we aimed at defining whether increased HIF1α and/or HIF2α, due to endothelial cell specific deletion of prolyl hydroxylase domain protein 2 (PHD2) under normoxic condition are involved in or required for the initiation and progression of pulmonary hypertension. Methods: PHD2, HIF1α and HIF2α conditional knockout mice were created. Right ventricle systolic pressures (RVSP), right ventricular hypertrophy by RV/(LV+S) ratios, and small pulmonary artery smooth muscle layer thickness were measured. Pulmonary arterial smooth muscle cells (PASMCs) and pulmonary arterial endothelial cells (PAECs) were isolated from wild type (WT) or knockout (KO) mice, followed with cell-based assays. Results: We report here that mice with targeted deletion of PHD2 developed severe pulmonary hypertension under normoxic condition. Conditional and inducible deletion of HIF2α in endothelial cells, but not smooth muscle cells, dramatically protected mice from hypoxia-induced pulmonary hypertension. HIF2α KO mice had significantly lower RVSP, RV/(LV+S) ratios, and displayed less pulmonary vascular remodeling when exposed to hypoxia compared to their WT mice. Conclusion: This work shows that the endothelium is responsible for the development of pulmonary hypertension and it demonstrates a crucial role of PHD2/HIF signaling for hypoxic response in pulmonary hypertension. These findings unveil temporally and spatially distinct functions for HIFs in the development of pulmonary hypertension.

scholarly journals P1505 Echocardiographic assessment of different pulmonary hypertension groups

2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
M Fontes Oliveira ◽  
M Trepa ◽  
R Costa ◽  
A Dias Frias ◽  
I Silveira ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Interventricular Septum ◽  
Pulmonary Vascular Disease ◽  
Eccentricity Index ◽  
Group 4 ◽  
Global Strain ◽  
Group 3 ◽  
Group 2 ◽  
Rv Function ◽  
Group 1

Abstract Introduction Noninvasive echocardiography evaluation of the right ventricle (RV) has been shown to have prognostic value in patients with pulmonary hypertension (PH). Different etiology groups might have different echocardiographic phenotypes. In this study, we aimed to study echocardiographic characterization of the different PH groups and its ability to predict pulmonary vascular disease severity. Methods We collected echocardiographic and right heart catheterization (RHC) data from 97 (75% female, age 65 ± 15 years) consecutive patients referred to an expert tertiary care referral PH centre from 12/2016 to 11/2018. Echocardiographic analysis was performed using Echo-Pac software from GE Healthcare®. Group 3 and 5 were not included in the group comparison analysis due to few patients included. Results Group 2 PH was the most frequent etiology of PH (35), followed by group 1 (26), group 4 (18), group 5 (3) and group 3 (2). The echocardiographic evaluation of this population as a whole showed borderline parameters of RV dysfunction (tricuspid annular plane systolic excursion (TAPSE) 18 ± 4 mm, fractional area change (FAC) 33 ± 10% and S’ tricuspid wave 10 ± 3 cm/sec). Mean RV global strain was -15 ± 5 and RV free wall strain was -17 ± 7. PH group 1 had a significantly lower FAC (26 ± 4%, p = 0.0025), higher eccentricity index (IE) (1.5 ± 0.1, p = 0.01), and more frequently RV outflow tract (RVOT) notching than other groups (62%, p = 0.012). Group 4 presented an intermedium echocardiographic phenotype between group 1 and 2, and showed more abnormal strain values than the other groups. Group 2 had fewer patients in sinus rhythm (atrial fibrillation in 34% of patients, p = 0.02), presented a thicker interventricular septum (11.3 ± 1.8, p = 0.014), a higher FAC (35 ± 3%, p = 0.0025), higher E mitral wave velocity (72 ± 6 cm/s, p < 0.001) and E/E’ ratio (12.7 ± 10.2, p = 0.006), and larger left (45 ± 3 cm3/m3, p < 0.01) and right atria (25 ± 2 cm2, p = 0.03). PH groups 1 and 4 had higher Pulmonary Vascular Resistance (PVR) and Pulmonary Mean Arterial Pressure (PMAP) values than group 2, which significantly correlated with echocardiographic RV function parameters as TAPSE, FAC, RV global strain and IE. In PH group 2, eccentricity index was the only predictor of PVR (β=4.1, p = 0.018). In this population, a left atria volume < 32.7 cm3/m2 (OR 4.25, CI 1.71 - 10.55) and a E/e’ ratio < 12 (OR 4.72, CI 2.05 - 10.87) predicted PECP < 15 mmHg. RV global strain > -17.1 predicted PVR > 3 wood (OR 3.46, CI 1.50 - 8.02) and PMAP > 20 mmHg (OR 4.92, CI 1.67 - 14.51). TAPSE < 18 mm predicted PVR > 3 wood (OR 7.41, CI 2.99 - 18.36, AUC 0.72). Conclusion Different PH groups present mild echocardiographic differences between them. PH group 1 presented with more echocardiographic signs of RV disfunction, and PH group 2 had higher FAC, E/E’ and larger right and left atria. RV function parameters predicted PVR in PH groups 1 and 4, and EI was the only predictor of PVR in PH group 2. Abstract P1505 Figure.

scholarly journals NDRG1 Targets TAF15 to Promote Endothelial Dysfunction and Hypoxia-Induced Pulmonary Hypertension

2021 ◽  
Author(s):  
Chengwei Li ◽  
Liang Dong ◽  
Ning Zhu ◽  
Xiujuan Zhang ◽  
Ruzetuoheti Yiminniyaze ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Endothelial Dysfunction ◽  
Vascular Remodeling ◽  
Tube Formation ◽  
Cell Counting ◽  
Dependent Manner ◽  
Rat Models ◽  
Chain Reactions

Abstract Background: The mechanism underlying vascular remodeling of hypoxia-induced pulmonary hypertension (HPH) is not fully elucidated. We hypothesized that hypoxia promotes expression of N-myc downstream regulated gene-1 (NDRG1) in human pulmonary arterial endothelial cells (HPAECs), which in turn leads to endothelial dysfunction and contributing to HPH. Methods: Lung samples were obtained from qualified patients and HPH rat models. Quantitative polymerase chain reactions, western blotting and immunohistochemistry were used to measure the expression of NDRG1. EdU incorporation assays, cell counting kit-8 (CCK-8) assays, transwell migration assays, and matrigel assays were conducted to detect the role of NDRG1 in HPACE function in vitro. HPH models were established in SD rats and were treated with plasmids expressing short hairpin RNAs (shRNAs) to silence NDRG1. The candidate binding partner(s) of NDRG1 was screened and validated via co-immunoprecipitation and immunofluorescence staining. Results: NDRG1 is up-regulated by hypoxia in a time-dependent manner in HPAECs. Expression of NDRG1 was increased in lung tissues of HPH patient and rat model. In vitro, silencing NDRG1 attenuated proliferation, migration and tube formation of HPAECs under hypoxia, while NDRG1 over-expression promoted these behaviors of HPAECs in normoxia. NDRG1 knock-down alleviated vascular remodeling and right ventricular hypertrophy in rat models of HPH. NDRG1 can directly interact with TATA-box binding protein associated factor 15 (TAF15) and promote its nuclear localization. Bioinformatics study found that Notch1 signaling was downstream of TAF15 in endothelial cells. TAF15 can promote HPAECs dysfunction via binding to Notch1 promoter region and subsequently increasing Notch1 expression. Conclusions: Taken together, hypoxia-induced up-regulation of NDRG1 contributes to endothelial dysfunction and HPH development through TAF15 upregulation of Notch1, suggesting the applicability of targeting NDRG1 in clinical treatment of HPH.

scholarly journals The reversal of pulmonary vascular remodeling through inhibition of p38 MAPK-alpha: a potential novel anti-inflammatory strategy in pulmonary hypertension

2015 ◽  
Vol 309 (4) ◽  
pp. L333-L347 ◽  
Author(s):  
Alistair C. Church ◽  
Damien H. Martin ◽  
Roger Wadsworth ◽  
Gareth Bryson ◽  
Andrew J. Fisher ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Disease ◽  
P38 Mapk ◽  
Human Disease ◽  
Vascular Remodeling ◽  
Pulmonary Vascular Disease ◽  
Rodent Models ◽  
In Vivo Models ◽  
Pulmonary Vascular Remodeling

The p38 mitogen-activated protein kinase (MAPK) system is increasingly recognized as an important inflammatory pathway in systemic vascular disease but its role in pulmonary vascular disease is unclear. Previous in vitro studies suggest p38 MAPKα is critical in the proliferation of pulmonary artery fibroblasts, an important step in the pathogenesis of pulmonary vascular remodeling (PVremod). In this study the role of the p38 MAPK pathway was investigated in both in vitro and in vivo models of pulmonary hypertension and human disease. Pharmacological inhibition of p38 MAPKα in both chronic hypoxic and monocrotaline rodent models of pulmonary hypertension prevented and reversed the pulmonary hypertensive phenotype. Furthermore, with the use of a novel and clinically available p38 MAPKα antagonist, reversal of pulmonary hypertension was obtained in both experimental models. Increased expression of phosphorylated p38 MAPK and p38 MAPKα was observed in the pulmonary vasculature from patients with idiopathic pulmonary arterial hypertension, suggesting a role for activation of this pathway in the PVremod A reduction of IL-6 levels in serum and lung tissue was found in the drug-treated animals, suggesting a potential mechanism for this reversal in PVremod. This study suggests that the p38 MAPK and the α-isoform plays a pathogenic role in both human disease and rodent models of pulmonary hypertension potentially mediated through IL-6. Selective inhibition of this pathway may provide a novel therapeutic approach that targets both remodeling and inflammatory pathways in pulmonary vascular disease.

scholarly journals Eplerenone Improves Pulmonary Vascular Remodeling and Hypertension by Inhibition of the Mineralocorticoid Receptor in Endothelial Cells

Hypertension ◽  
2021 ◽  
Author(s):  
Jessica Kowalski ◽  
Lisa Deng ◽  
Chiara Suennen ◽  
Duygu Koca ◽  
David Meral ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Remodeling ◽  
Mineralocorticoid Receptor ◽  
Chronic Hypoxia ◽  
Cell Type ◽  
Pulmonary Vascular Remodeling ◽  
Cell Type Specific

Pulmonary hypertension is characterized by progressive remodeling of the pulmonary arteries, however, this is not therapeutically targeted yet. Aldosterone and the MR (mineralocorticoid receptor) are key drivers of cardiovascular disease, and there is a growing body of evidence suggesting a role in pulmonary hypertension. Thus, the aim of this study was to investigate the impact of cell type-specific deletion of MR on pulmonary vascular remodeling. To induce pulmonary hypertension, mice were exposed to chronic hypoxia for 6 weeks. Treatment with the MR antagonist eplerenone attenuated pulmonary vascular remodeling, hypertension, and right ventricular dysfunction. In contrast, aldosterone infusion via osmotic minipumps induced pulmonary vascular remodeling. We created 4 different mouse models with cell type-specific MR deletion in smooth muscle cells, endothelial cells, macrophages, or fibroblasts and exposed them to chronic hypoxia. MR deletion from endothelial cells fully recapitulated the beneficial effects of eplerenone while MR deletion from other cell types had no detectable effect on pulmonary vascular remodeling. RNA-seq from isolated MR-deficient and wildtype pulmonary endothelial cells revealed differentially expressed genes as potential downstream mediators of MR related to pulmonary hypertension, including genes related to the endothelin signaling pathway. MR antagonists improve hypoxia-induced pulmonary vascular remodeling via inhibition of MR in endothelial cells but independent from MR in smooth muscle cells, fibroblasts, or macrophages. The results from this study provide the basis for future investigation of potential downstream mediators of MR involved in pulmonary hypertension and further support the clinical evaluation of MR antagonists in pulmonary hypertension.

scholarly journals Myeloid-Derived Suppressor Cells and Pulmonary Hypertension

2018 ◽  
Vol 19 (8) ◽  
pp. 2277
Author(s):  
Andrew Bryant ◽  
Borna Mehrad ◽  
Todd Brusko ◽  
James West ◽  
Lyle Moldawer
Keyword(s):  
Pulmonary Hypertension ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Myeloid Derived Suppressor Cells ◽  
Pulmonary Vascular Remodeling ◽  
Adaptive Immune ◽  
Cell Changes ◽  
Transcription Factor Signaling

Myeloid–derived suppressor cells (MDSCs) comprised a heterogeneous subset of bone marrow–derived myeloid cells, best studied in cancer research, that are increasingly implicated in the pathogenesis of pulmonary vascular remodeling and the development of pulmonary hypertension. Stem cell transplantation represents one extreme interventional strategy for ablating the myeloid compartment but poses a number of translational challenges. There remains an outstanding need for additional therapeutic targets to impact MDSC function, including the potential to alter interactions with innate and adaptive immune subsets, or alternatively, alter trafficking receptors, metabolic pathways, and transcription factor signaling with readily available and safe drugs. In this review, we summarize the current literature on the role of myeloid cells in the development of pulmonary hypertension, first in pulmonary circulation changes associated with myelodysplastic syndromes, and then by examining intrinsic myeloid cell changes that contribute to disease progression in pulmonary hypertension. We then outline several tractable targets and pathways relevant to pulmonary hypertension via MDSC regulation. Identifying these MDSC-regulated effectors is part of an ongoing effort to impact the field of pulmonary hypertension research through identification of myeloid compartment-specific therapeutic applications in the treatment of pulmonary vasculopathies.

scholarly journals Optimization of combined measures of airway physiology and cardiovascular hemodynamics in mice

2020 ◽  
Vol 10 (1) ◽  
pp. 204589402091293 ◽  
Author(s):  
Katrina W. Kopf ◽  
Julie W. Harral ◽  
Emily A. Staker ◽  
Megan E. Summers ◽  
Irina Petrache ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Lung Disease ◽  
Chronic Lung Disease ◽  
Chronic Obstructive ◽  
Murine Models ◽  
Comprehensive Overview ◽  
Cardiovascular Hemodynamics ◽  
Chronic Lung Diseases ◽  
Group 3 ◽  
Airway Physiology

Pulmonary hypertension may arise as a complication of chronic lung disease typically associated with tissue hypoxia, as well as infectious agents or injury eliciting a type 2 immune response. The onset of pulmonary hypertension in this setting (classified as Group 3) often complicates treatment and worsens prognosis of chronic lung disease. Chronic lung diseases such as chronic obstructive lung disease (COPD), emphysema, and interstitial lung fibrosis impair airflow and alter lung elastance in addition to affecting pulmonary vascular hemodynamics that may culminate in right ventricle dysfunction. To date, functional endpoints in murine models of chronic lung disease have typically been limited to separately measuring airway and lung parenchyma physiology. These approaches may be lengthy and require a large number of animals per experiment. Here, we provide a detailed protocol for combined assessment of airway physiology with cardiovascular hemodynamics in mice. Ultimately, a comprehensive overview of pulmonary function in murine models of injury and disease will facilitate the integration of studies of the airway and vascular biology necessary to understand underlying pathophysiology of Group 3 pulmonary hypertension.

Disrupted pulmonary vascular development and pulmonary hypertension in transgenic mice overexpressing transforming growth factor-α

2003 ◽  
Vol 285 (5) ◽  
pp. L1046-L1054 ◽  
Author(s):  
Timothy D. Le Cras ◽  
William D. Hardie ◽  
Karen Fagan ◽  
Jeffrey A. Whitsett ◽  
Thomas R. Korfhagen
Keyword(s):  
Pulmonary Hypertension ◽  
Growth Factor ◽  
Transgenic Mice ◽  
Vascular Disease ◽  
Vascular Remodeling ◽  
Transforming Growth Factor ◽  
Vascular Development ◽  
Angiogenic Factor ◽  
Pulmonary Vascular Disease ◽  
Pulmonary Vascular Development

Pulmonary vascular disease plays a major role in morbidity and mortality in infant and adult lung diseases in which increased levels of transforming growth factor (TGF)-α and its receptor EGFR have been associated. The aim of this study was to determine whether overexpression of TGF-α disrupts pulmonary vascular development and causes pulmonary hypertension. Lung-specific expression of TGF-α in transgenic mice was driven with the human surfactant protein (SP)-C promoter. Pulmonary arteriograms and arterial counts show that pulmonary vascular development was severely disrupted in TGF-α mice. TGF-α mice developed severe pulmonary hypertension and vascular remodeling characterized by abnormally extensive muscularization of small pulmonary arteries. Pulmonary vascular development was significantly improved and pulmonary hypertension and vascular remodeling were prevented in bitransgenic mice expressing both TGF-α and a dominant-negative mutant EGF receptor under the control of the SP-C promoter. Vascular endothelial growth factor (VEGF-A), an important angiogenic factor produced by the distal epithelium, was decreased in the lungs of TGF-α adults and in the lungs of infant TGF-α mice before detectable abnormalities in pulmonary vascular development. Hence, overexpression of TGF-α caused severe pulmonary vascular disease, which was mediated through EGFR signaling in distal epithelial cells. Reductions in VEGF may contribute to the pathogenesis of pulmonary vascular disease in TGF-α mice.

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