scholarly journals The alveolar epithelial cells are involved in pulmonary vascular remodeling and constriction of hypoxic pulmonary hypertension

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yanxia Wang ◽  
Xiaoming Li ◽  
Wen Niu ◽  
Jian Chen ◽  
Bo Zhang ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Pulmonary Hypertension ◽  
Epithelial Cells ◽  
Pulmonary Artery ◽  
Vascular Remodeling ◽  
Culture Medium ◽  
Alveolar Epithelial Cells ◽  
Pulmonary Vascular Remodeling ◽  
Hypoxic Pulmonary Hypertension ◽  
Alveolar Epithelial

Abstract Background Hypoxic pulmonary hypertension (HPH) is a common type of pulmonary hypertension and characterized by pulmonary vascular remodeling and constriction. Alveolar epithelial cells (AECs) primarily sense alveolar hypoxia, but the role of AECs in HPH remains unclear. In this study, we explored whether AECs are involved in pulmonary vascular remodeling and constriction. Methods In the constructed rat HPH model, hemodynamic and morphological characteristics were measured. By treating AECs with hypoxia, we further detected the levels of superoxide dismutase 2 (SOD2), catalase (CAT), reactive oxygen species (ROS) and hydrogen peroxide (H2O2), respectively. To detect the effects of AECs on pulmonary vascular remodeling and constriction, AECs and pulmonary artery smooth cells (PASMCs) were co-cultured under hypoxia, and PASMCs and isolated pulmonary artery (PA) were treated with AECs hypoxic culture medium. In addition, to explore the mechanism of AECs on pulmonary vascular remodeling and constriction, ROS inhibitor N-acetylcysteine (NAC) was used. Results Hypoxia caused pulmonary vascular remodeling and increased pulmonary artery pressure, but had little effect on non-pulmonary vessels in vivo. Meanwhile, in vitro, hypoxia promoted the imbalance of SOD2 and CAT in AECs, leading to increased ROS and hydrogen peroxide (H2O2) production in the AECs culture medium. In addition, AECs caused the proliferation of co-cultured PASMCs under hypoxia, and the hypoxic culture medium of AECs enhanced the constriction of isolated PA. However, treatment with ROS inhibitor NAC effectively alleviated the above effects. Conclusion The findings of present study demonstrated that AECs were involved in pulmonary vascular remodeling and constriction under hypoxia by paracrine H2O2 into the pulmonary vascular microenvironment.

scholarly journals Alveolar Epithelial Cells Involved in Pulmonary Vascular Remodeling and Constriction of Hypoxic Pulmonary Hypertension

2020 ◽  
Author(s):  
Yanxia Wang ◽  
Xiaoming Li ◽  
Wen Niu ◽  
Jian Chen ◽  
Bo Zhang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Vascular Remodeling ◽  
Culture Medium ◽  
Alveolar Epithelial Cells ◽  
Oxygen Species ◽  
Pulmonary Vascular Remodeling ◽  
Alveolar Epithelial ◽  
Isolated Pulmonary Artery ◽  
Superoxide Dismutase 2

Abstract Background: Hypoxic pulmonary hypertension (HPH) is a common type of pulmonary hypertension. Alveolar epithelial cells (AECs) are the first to perceive hypoxia of alveolar, however, the role of AECs in HPH remain unclear. HPH is characterized by pulmonary vascular remodeling and constriction. The present study was to whether AECs was involved in pulmonary vascular remodeling and constriction.Methods: Rat HPH models were built and pulmonary artery smooth cells (PASMCs) and AECs were treatment with hypoxia. Hemodynamic and morphological indicators were measured in samples from rat HPH models. Superoxide dismutase 2 (SOD2), catalase (CAT) and reactive oxygen species (ROS) were detected in AECs or AECs culture medium. To find out the effect of AECs on pulmonary vascular remodeling and constriction, AECs and PASMCs were co-cultured under hypoxia, PASMCs and isolated pulmonary artery (PA) were treatment with AECs hypoxic culture medium. To explore the mechanism of AECs on pulmonary vascular remodeling and constriction, ROS inhibitor N-acetylcysteine (NAC) was used.Results: In vivo, hypoxia resulted in elevation in pulmonary vascular remodeling and pressure, but had no effect on non-pulmonary vascular. In vitro, hypoxia caused an imbalance of superoxide dismutase 2 (SOD2) and catalase (CAT) and an increase of reactive oxygen species (ROS) in AECs, as well as an increase of hydrogen peroxide (H2O2) in AECs culture medium. Also, AECs led to pulmonary artery smooth cells (PASMCs) proliferation under hypoxia by co-culture or substituting culture medium. AECs hypoxic culture medium enhanced the constriction of isolated pulmonary artery (PA). Further, these responses were abrogated by ROS inhibitor N-acetylcysteine (NAC). Conclusion: The findings of present study demonstrated that AECs involved in pulmonary vascular remodeling and constriction under hypoxia by secreting H2O2 to the pulmonary microenvironment.

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.

Hypoxia-Induced Changes in the Mechanical Properties of the Mouse Pulmonary Artery

2003 ◽  
Author(s):  
Ryan W. Kobs ◽  
Nidal E. Muvarak ◽  
Naomi C. Chesler
Keyword(s):  
Mechanical Properties ◽  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Vascular Remodeling ◽  
Hypobaric Hypoxia ◽  
Vessel Wall ◽  
Main Pulmonary Artery ◽  
Collagen Content ◽  
Pulmonary Vascular Remodeling ◽  
Induced Changes

Hypobaric hypoxia produces pulmonary hypertension in mice which causes pulmonary vascular remodeling. To study the biomechanics of this process, mice were exposed to hypoxia for 0-(control), 10-, and 15-days. Using a pressurized arteriograph system, mechanical properties of the main pulmonary artery were measured and compared to the biological changes in the vessel wall measured histologically. 10- and 15-day hypoxic vessels were significantly stiffer when compared to 0-day vessels. This stiffness correlated with greater elastin and collagen content in the vessel wall.

scholarly journals TRB3 mediates vascular remodeling by activating the MAPK signaling pathway in hypoxic pulmonary hypertension

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Xiaopei Cao ◽  
Xiaoyu Fang ◽  
Mingzhou Guo ◽  
Xiaochen Li ◽  
Yuanzhou He ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Protein Expression ◽  
Signaling Pathway ◽  
P38 Mapk ◽  
Vascular Remodeling ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Clinical Samples ◽  
Hypoxic Pulmonary Hypertension

Abstract Background Hypoxic pulmonary hypertension (PH) is a refractory pulmonary vascular remodeling disease, and the efficiency of current PH treatment strategies is unsatisfactory. Tribbles homolog 3 (TRB3), a member of the pseudokinase family, is upregulated in diverse types of cellular stresses and functions as either a pro-proliferative or pro-apoptotic factor depending on the specific microenvironment. The regulatory mechanisms of TRB3 in hypoxic PH are poorly understood. Methods We performed studies using TRB3-specific silencing and overexpressing lentiviral vectors to investigate the potential roles of TRB3 on hypoxic pulmonary artery smooth muscle cells (PASMCs). Adeno-associated virus type 1(AVV1) vectors encoding short-hairpin RNAs against rat TRB3 were used to assess the role of TRB3 on hypoxic PH. TRB3 protein expression in PH patients was explored in clinical samples by western blot analysis. Results The results of whole-rat genome oligo microarrays showed that the expression of TRB3 and endoplasmic reticulum stress (ERS)-related genes was upregulated in hypoxic PASMCs. TRB3 protein expression was significantly upregulated by hypoxia and thapsigargin. In addition, 4-PBA and 4μ8C, both inhibitors of ERS, decreased the expression of TRB3. TRB3 knockdown promoted apoptosis and damaged the proliferative and migratory abilities of hypoxic PASMCs as well as inhibited activation of the MAPK signaling pathway. TRB3 overexpression stimulated the proliferation and migration of PASMCs but decreased the apoptosis of PASMCs, which was partly reversed by specific inhibitors of ERK, JNK and p38 MAPK. The Co-IP results revealed that TRB3 directly interacts with ERK, JNK, and p38 MAPK. Knockdown of TRB3 in rat lung tissue reduced the right ventricular systolic pressure and decreased pulmonary medial wall thickness in hypoxic PH model rats. Further, the expression of TRB3 in lung tissues was higher in patients with PH compared with those who have normal pulmonary artery pressure. Conclusions TRB3 was upregulated in hypoxic PASMCs and was affected by ERS. TRB3 plays a key role in the pathogenesis of hypoxia-induced PH by binding and activating the ERK, JNK, and p38 MAPK pathways. Thus, TRB3 might be a promising target for the treatment of hypoxic PH.

scholarly journals Pulmonary Artery Smooth Muscle Cell Senescence Promotes the Proliferation of PASMCs by Paracrine IL-6 in Hypoxia-Induced Pulmonary Hypertension

2021 ◽  
Vol 12 ◽  
Author(s):  
Ai-Ping Wang ◽  
Fang Yang ◽  
Ying Tian ◽  
Jian-Hui Su ◽  
Qing Gu ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Remodeling ◽  
Pathophysiological Mechanism ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Artery Smooth Muscle ◽  
Active Substances

Pulmonary hypertension (PH) is a critical and dangerous disease in cardiovascular system. Pulmonary vascular remodeling is an important pathophysiological mechanism for the development of pulmonary arterial hypertension. Pulmonary artery smooth muscle cell (PASMC) proliferation, hypertrophy, and enhancing secretory activity are the main causes of pulmonary vascular remodeling. Previous studies have proven that various active substances and inflammatory factors, such as interleukin 6 (IL-6), IL-8, chemotactic factor for monocyte 1, etc., are involved in pulmonary vascular remodeling in PH. However, the underlying mechanisms of these active substances to promote the PASMC proliferation remain to be elucidated. In our study, we demonstrated that PASMC senescence, as a physiopathologic mechanism, played an essential role in hypoxia-induced PASMC proliferation. In the progression of PH, senescence PASMCs could contribute to PASMC proliferation via increasing the expression of paracrine IL-6 (senescence-associated secretory phenotype). In addition, we found that activated mTOR/S6K1 pathway can promote PASMC senescence and elevate hypoxia-induced PASMC proliferation. Further study revealed that the activation of mTOR/S6K1 pathway was responsible for senescence PASMCs inducing PASMC proliferation via paracrine IL-6. Targeted inhibition of PASMC senescence could effectively suppress PASMC proliferation and relieve pulmonary vascular remodeling in PH, indicating a potential for the exploration of novel anti-PH strategies.

NPS2143 Modulates the Phenotypic Switching of PASMCs by Inhibiting Autophagy in Hypoxia-Induced Pulmonary Hypertension

2021 ◽  
Vol 8 (2) ◽  
Author(s):  
Wang L ◽  
◽  
Shao H ◽  
Che B ◽  
Wang N ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Western Blot ◽  
Vascular Remodeling ◽  
Pulmonary Artery Hypertension ◽  
Phenotypic Switching ◽  
Pulmonary Vascular Remodeling

Background and Objectives: Pulmonary Artery Hypertension (PAH) is considered as a malignant tumor in cardiovascular disease. Our previous study found that Calcium-Sensing Receptor (CaSR) is involved in pulmonary vascular remodeling in hypoxic pulmonary hypertension (HPH). However, the relationship of Pulmonary Artery Smooth Muscle Cell (PASMC) phenotypic switching, proliferation, and autophagy in CaSR-related HPH remain unclear. The purpose of this study was to detect the role of a CaSR antagonist, NPS2143, on the vascular remodeling by autophagy modulation under hypoxia. Methods: Hypoxic rat PAH model were simulated in vivo. Meanwhile, mean Pulmonary Artery Pressure (mPAP) was measured while RVI, WT%, and WA% indices were calculated. Immunohistochemistry and Western blot were used to detect phenotypic switching and cell proliferation in pulmonary arteriole. Cell viability was determined in vitro by CCK8 and cell cycle. Cell proliferation, phenotypic switching, autophagy level and PI3K/Akt/mTOR pathways were investigated in human PASMCs through mRNA or Western blot methods. Results: Rats with hypoxic-induced PAH had an increased mPAP, RVI, WT% and WA%. Moreover, expression of CaSR was significantly increased, followed by activation of autophagy (increased LC3b and decreased p62), phenotypic switching of PASMCs (reduced calponin, SMA-a and increased OPN) and pulmonary vascular remodeling. However, NPS2143 weakened these hypoxic effects. The results using hypoxic-induced human PASMCs confirmed that NPS2143 suppressed autophagy and reversed phenotypic switching in vitro by inhibiting PI3K/Akt/mTOR pathways. Conclusions: Our study demonstrates that NPS2143 was conducive to inhibit the proliferation and reverse phenotypic switching of PASMCs by regulating autophagy levels in HPH and vascular remodeling.

scholarly journals Involvement of RhoA/Rho kinase signaling in protection against monocrotaline-induced pulmonary hypertension in pneumonectomized rats by dehydroepiandrosterone

2008 ◽  
Vol 295 (1) ◽  
pp. L71-L78 ◽  
Author(s):  
Noriyuki Homma ◽  
Tetsutaro Nagaoka ◽  
Vijaya Karoor ◽  
Masatoshi Imamura ◽  
Laimute Taraseviciene-Stewart ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Protein Expression ◽  
Vascular Remodeling ◽  
Rho Kinase ◽  
Related Protein ◽  
Pulmonary Vascular Remodeling ◽  
Naturally Occurring ◽  
Dhea Treatment ◽  
Induced Changes

RhoA/Rho kinase (ROCK) signaling plays a key role in the pathogenesis of experimental pulmonary hypertension (PH). Dehydroepiandrosterone (DHEA), a naturally occurring steroid hormone, effectively inhibits chronic hypoxic PH, but the responsible mechanisms are unclear. This study tested whether DHEA was also effective in treating monocrotaline (MCT)-induced PH in left pneumonectomized rats and whether inhibition of RhoA/ROCK signaling was involved in the protective effect of DHEA. Three weeks after MCT injection, pneumonectomized rats developed PH with severe vascular remodeling, including occlusive neointimal lesions in pulmonary arterioles. In lungs from these animals, we detected cleaved (constitutively active) ROCK I as well as increases in activities of RhoA and ROCK and increases in ROCK II protein expression. Chronic DHEA treatment (1%, by food for 3 wk) markedly inhibited the MCT-induced PH (mean pulmonary artery pressures after treatment with 0% and 1% DHEA were 33 ± 5 and 16 ± 1 mmHg, respectively) and severe pulmonary vascular remodeling in pneumonectomized rats. The MCT-induced changes in RhoA/ROCK-related protein expression were nearly normalized by DHEA. A 3-wk DHEA treatment (1%) started 3 wk after MCT injection completely inhibited the progression of PH (mean pulmonary artery pressures after treatment with 0% and 1% DHEA were 47 ± 3 and 30 ± 3 mmHg, respectively), and this treatment also resulted in 100% survival in contrast to 30% in DHEA-untreated rats. These results suggest that inhibition of RhoA/ROCK signaling, including the cleavage and constitutive activation of ROCK I, is an important component of the impressive protection of DHEA against MCT-induced PH in pneumonectomized rats.

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