Pulmonary Hypertension: Pathophysiology and Signaling Pathways

2013 ◽  
pp. 31-58 ◽  
Author(s):  
Bradley A. Maron ◽  
Joseph Loscalzo
Keyword(s):  
Pulmonary Hypertension ◽  
Signaling Pathways

scholarly journals The role of inflammation in hypoxic pulmonary hypertension: from cellular mechanisms to clinical phenotypes

2015 ◽  
Vol 308 (3) ◽  
pp. L229-L252 ◽  
Author(s):  
Steven C. Pugliese ◽  
Jens M. Poth ◽  
Mehdi A. Fini ◽  
Andrea Olschewski ◽  
Karim C. El Kasmi ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Signaling Pathways ◽  
Vascular Remodeling ◽  
Mesenchymal Cells ◽  
World Health ◽  
Small Subset ◽  
Cellular Interactions ◽  
Pulmonary Vascular Remodeling ◽  
Hypoxic Pulmonary Hypertension ◽  
Group I

Hypoxic pulmonary hypertension (PH) comprises a heterogeneous group of diseases sharing the common feature of chronic hypoxia-induced pulmonary vascular remodeling. The disease is usually characterized by mild to moderate pulmonary vascular remodeling that is largely thought to be reversible compared with the progressive irreversible disease seen in World Health Organization (WHO) group I disease. However, in these patients, the presence of PH significantly worsens morbidity and mortality. In addition, a small subset of patients with hypoxic PH develop “out-of-proportion” severe pulmonary hypertension characterized by pulmonary vascular remodeling that is irreversible and similar to that in WHO group I disease. In all cases of hypoxia-related vascular remodeling and PH, inflammation, particularly persistent inflammation, is thought to play a role. This review focuses on the effects of hypoxia on pulmonary vascular cells and the signaling pathways involved in the initiation and perpetuation of vascular inflammation, especially as they relate to vascular remodeling and transition to chronic irreversible PH. We hypothesize that the combination of hypoxia and local tissue factors/cytokines (“second hit”) antagonizes tissue homeostatic cellular interactions between mesenchymal cells (fibroblasts and/or smooth muscle cells) and macrophages and arrests these cells in an epigenetically locked and permanently activated proremodeling and proinflammatory phenotype. This aberrant cellular cross-talk between mesenchymal cells and macrophages promotes transition to chronic nonresolving inflammation and vascular remodeling, perpetuating PH. A better understanding of these signaling pathways may lead to the development of specific therapeutic targets, as none are currently available for WHO group III disease.

scholarly journals New Insights Into HIMF (Hypoxia-Induced Mitogenic Factor)-Mediated Signaling Pathways in Pulmonary Hypertension

2019 ◽  
Vol 39 (12) ◽  
pp. 2451-2453 ◽  
Author(s):  
Olivier Boucherat ◽  
Roxane Paulin ◽  
Steeve Provencher ◽  
Sébastien Bonnet
Keyword(s):  
Pulmonary Hypertension ◽  
Signaling Pathways ◽  
Mitogenic Factor

scholarly journals Signaling Pathways Involved in the Development of Bronchopulmonary Dysplasia and Pulmonary Hypertension

Children ◽  
2020 ◽  
Vol 7 (8) ◽  
pp. 100
Author(s):  
Rajamma Mathew
Keyword(s):  
Pulmonary Hypertension ◽  
Growth Factor ◽  
Signaling Pathways ◽  
Bronchopulmonary Dysplasia ◽  
Premature Infants ◽  
Animal Experiments ◽  
Tissue Growth ◽  
Inflammatory Stress ◽  
Fibroblast Growth Factor 10 ◽  
Endothelial Growth Factor

The alveolar and vascular developmental arrest in the premature infants poses a major problem in the management of these infants. Although, with the current management, the survival rate has improved in these infants, but bronchopulmonary dysplasia (BPD) is a serious complication associated with a high mortality rate. During the neonatal developmental period, these infants are vulnerable to stress. Hypoxia, hyperoxia, and ventilation injury lead to oxidative and inflammatory stress, which induce further damage in the lung alveoli and vasculature. Development of pulmonary hypertension (PH) in infants with BPD worsens the prognosis. Despite considerable progress in the management of premature infants, therapy to prevent BPD is not yet available. Animal experiments have shown deregulation of multiple signaling factors such as transforming growth factorβ (TGFβ), connective tissue growth factor (CTGF), fibroblast growth factor 10 (FGF10), vascular endothelial growth factor (VEGF), caveolin-1, wingless & Int-1 (WNT)/β-catenin, and elastin in the pathogenesis of BPD. This article reviews the signaling pathways entailed in the pathogenesis of BPD associated with PH and the possible management.

scholarly journals Opposing Effects of TGFβ and BMP in the Pulmonary Vasculature in Congenital Diaphragmatic Hernia

2021 ◽  
Vol 8 ◽  
Author(s):  
Daphne S. Mous ◽  
Marjon J. Buscop-van Kempen ◽  
Rene M. H. Wijnen ◽  
Dick Tibboel ◽  
Rory E. Morty ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Congenital Diaphragmatic Hernia ◽  
Signaling Pathways ◽  
Diaphragmatic Hernia ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Muscle Layer ◽  
Pulmonary Vasculature ◽  
Sprague Dawley ◽  
Protein Levels

Background: Pulmonary hypertension is the major cause of morbidity and mortality in congenital diaphragmatic hernia (CDH). Mutations in several genes that encode signaling molecules of the transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) pathways have previously been associated with CDH. Since studies on the activation of these pathways in CDH are scarce, and have yielded inconsistent conclusions, the downstream activity of both pathways was assessed in the nitrofen-CDH rat model.Methods and Results: Pregnant Sprague-Dawley rats were treated with nitrofen at embryonic day (E) 9.5 to induce CDH in offspring. At E21, lungs were screened for the expression of key factors of both signaling pathways, at both the mRNA transcript and protein levels. Subsequently, paying particular attention to the pulmonary vasculature, increased phosphorylation of SMAD2, and decreased phosphorylation of Smad5 was noted in the muscular walls of small pulmonary vessels, by immunohistochemistry. This was accompanied by increased proliferation of constituent cells of the smooth muscle layer of these vessels.Conclusions: Increased activation of the TGFβ pathway and decreased activation of the BMP pathway in the pulmonary vasculature of rats with experimentally-induced CDH, suggesting that the deregulated of these important signaling pathways may underlie the development of pulmonary hypertension in CDH.

scholarly journals Notch4 mediates vascular remodeling via ERK/JNK/P38 MAPK signaling pathways in hypoxic pulmonary hypertension

2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Mingzhou Guo ◽  
Mengzhe Zhang ◽  
Xiaopei Cao ◽  
Xiaoyu Fang ◽  
Ke Li ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Signaling Pathways ◽  
P38 Mapk ◽  
Vascular Remodeling ◽  
Cell Surface Receptor ◽  
Cell Counting ◽  
Pulmonary Vascular Remodeling ◽  
Hypoxic Pulmonary Hypertension ◽  
And Migration

Abstract Background Hypoxic pulmonary hypertension (HPH) is a chronic progressive advanced disorder pathologically characterized by pulmonary vascular remodeling. Notch4 as a cell surface receptor is critical for vascular development. However, little is known about the role and mechanism of Notch4 in the development of hypoxic vascular remodeling. Methods Lung tissue samples were collected to detect the expression of Notch4 from patients with HPH and matched controls. Human pulmonary artery smooth muscle cells (HPASMCs) were cultured in hypoxic and normoxic conditions. Real-time quantitative PCR and western blotting were used to examine the mRNA and protein levels of Notch4. HPASMCs were transfected with small interference RNA (siRNA) against Notch4 or Notch4 overexpression plasmid, respectively. Cell viability, cell proliferation, apoptosis, and migration were assessed using Cell Counting Kit-8, Edu, Annexin-V/PI, and Transwell assay. The interaction between Notch4 and ERK, JNK, P38 MAPK were analyzed by co-immunoprecipitation. Adeno-associated virus 1-mediated siRNA against Notch4 (AAV1-si-Notch4) was injected into the airways of hypoxic rats. Right ventricular systolic pressure (RVSP), right ventricular hypertrophy and pulmonary vascular remodeling were evaluated. Results In this study, we demonstrate that Notch4 is highly expressed in the media of pulmonary vascular and is upregulated in lung tissues from patients with HPH and HPH rats compared with control groups. In vitro, hypoxia induces the high expression of Delta-4 and Notch4 in HPASMCs. The increased expression of Notch4 promotes HPASMCs proliferation and migration and inhibits cells apoptosis via ERK, JNK, P38 signaling pathways. Furthermore, co-immunoprecipitation result elucidates the interaction between Notch4 and ERK/JNK/P38. In vivo, silencing Notch4 partly abolished the increase in RVSP and pulmonary vascular remodeling caused by hypoxia in HPH rats. Conclusions These findings reveal an important role of the Notch4-ERK/JNK/P38 MAPK axis in hypoxic pulmonary remodeling and provide a potential therapeutic target for patients with HPH.

scholarly journals Genetic Ablation of PDGF-Dependent Signaling Pathways Abolishes Vascular Remodeling and Experimental Pulmonary Hypertension

2015 ◽  
Vol 35 (5) ◽  
pp. 1236-1245 ◽  
Author(s):  
Henrik ten Freyhaus ◽  
Eva M. Berghausen ◽  
Wiebke Janssen ◽  
Maike Leuchs ◽  
Mario Zierden ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Signaling Pathways ◽  
Vascular Remodeling ◽  
Genetic Ablation

scholarly journals Crosstalk between the Akt/mTORC1 and NF-κB signaling pathways promotes hypoxia-induced pulmonary hypertension by increasing DPP4 expression in PASMCs

2019 ◽  
Vol 40 (10) ◽  
pp. 1322-1333 ◽  
Author(s):  
Ying Li ◽  
Li Yang ◽  
Liang Dong ◽  
Zhi-wei Yang ◽  
Jing Zhang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Signaling Pathways

scholarly journals PPARγ increases HUWE1 to attenuate NF-κB/p65 and sickle cell disease with pulmonary hypertension

2021 ◽  
Vol 5 (2) ◽  
pp. 399-413
Author(s):  
Andrew J. Jang ◽  
Sarah S. Chang ◽  
Changwon Park ◽  
Choon-Myung Lee ◽  
Raymond L. Benza ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Endothelial Dysfunction ◽  
Sickle Cell Disease ◽  
Signaling Pathways ◽  
Sickle Cell ◽  
Peroxisome Proliferator ◽  
Cell Disease ◽  
Littermate Control

Abstract Sickle cell disease (SCD)-associated pulmonary hypertension (PH) causes significant morbidity and mortality. Here, we defined the role of endothelial specific peroxisome proliferator-activated receptor γ (PPARγ) function and novel PPARγ/HUWE1/miR-98 signaling pathways in the pathogenesis of SCD-PH. PH and right ventricular hypertrophy (RVH) were increased in chimeric Townes humanized sickle cell (SS) mice with endothelial-targeted PPARγ knockout (SSePPARγKO) compared with chimeric littermate control (SSLitCon). Lung levels of PPARγ, HUWE1, and miR-98 were reduced in SSePPARγKO mice compared with SSLitCon mice, whereas SSePPARγKO lungs were characterized by increased levels of p65, ET-1, and VCAM1. Collectively, these findings indicate that loss of endothelial PPARγ is sufficient to increase ET-1 and VCAM1 that contribute to endothelial dysfunction and SCD-PH pathogenesis. Levels of HUWE1 and miR-98 were decreased, and p65 levels were increased in the lungs of SS mice in vivo and in hemin-treated human pulmonary artery endothelial cells (HPAECs) in vitro. Although silencing of p65 does not regulate HUWE1 levels, the loss of HUWE1 increased p65 levels in HPAECs. Overexpression of PPARγ attenuated hemin-induced reductions of HUWE1 and miR-98 and increases in p65 and endothelial dysfunction. Similarly, PPARγ activation attenuated baseline PH and RVH and increased HUWE1 and miR-98 in SS lungs. In vitro, hemin treatment reduced PPARγ, HUWE1, and miR-98 levels and increased p65 expression, HPAEC monocyte adhesion, and proliferation. These derangements were attenuated by pharmacological PPARγ activation. Targeting these signaling pathways can favorably modulate a spectrum of pathobiological responses in SCD-PH pathogenesis, highlighting novel therapeutic targets in SCD pulmonary vascular dysfunction and PH.

A compendium of G-protein–coupled receptors and cyclic nucleotide regulation of adipose tissue metabolism and energy expenditure

2020 ◽  
Vol 134 (5) ◽  
pp. 473-512 ◽  
Author(s):  
Ryan P. Ceddia ◽  
Sheila Collins
Keyword(s):  
Adipose Tissue ◽  
Energy Expenditure ◽  
Signaling Pathways ◽  
G Protein ◽  
Uncoupling Protein ◽  
Beige Adipocytes ◽  
Nucleotide Regulation ◽  
Ucp1 Expression ◽  
Thermogenic Adipocytes ◽  
G Protein Coupled

Abstract With the ever-increasing burden of obesity and Type 2 diabetes, it is generally acknowledged that there remains a need for developing new therapeutics. One potential mechanism to combat obesity is to raise energy expenditure via increasing the amount of uncoupled respiration from the mitochondria-rich brown and beige adipocytes. With the recent appreciation of thermogenic adipocytes in humans, much effort is being made to elucidate the signaling pathways that regulate the browning of adipose tissue. In this review, we focus on the ligand–receptor signaling pathways that influence the cyclic nucleotides, cAMP and cGMP, in adipocytes. We chose to focus on G-protein–coupled receptor (GPCR), guanylyl cyclase and phosphodiesterase regulation of adipocytes because they are the targets of a large proportion of all currently available therapeutics. Furthermore, there is a large overlap in their signaling pathways, as signaling events that raise cAMP or cGMP generally increase adipocyte lipolysis and cause changes that are commonly referred to as browning: increasing mitochondrial biogenesis, uncoupling protein 1 (UCP1) expression and respiration.

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