Effects of Estrogen on Pulmonary Vascular Remodeling in Pulmonary Artery Hypertension

2013 ◽  
Author(s):  
Aiping Liu ◽  
Naomi Chesler
Keyword(s):  
Pulmonary Artery ◽  
Progressive Increase ◽  
Pulmonary Artery Hypertension ◽  
Pulmonary Vascular Remodeling ◽  
Vegf Inhibitor ◽  
Vascular Impedance ◽  
Pulmonary Arterial ◽  
The Relationship

Pulmonary artery hypertension (PAH) is a female dominant, fatal disease characterized by progressive increase of pulmonary vascular resistance and loss of compliance. The role of estrogen in these pulmonary vascular changes with PAH progression remains unclear. Our objective was to study the effects of estrogen on pulmonary arterial (PA) remodeling in a mouse model of progressive PAH, created via a combination of a VEGF inhibitor Sugen and chronic hypoxia (SuHx). To quantify PA hemodynamics, we measured in vivo pressure and flow simultaneously in live mice in order to obtain pulmonary vascular impedance, a comprehensive measure of RV afterload. Our results demonstrate that estrogen modifies the relationship between PA resistance and compliance by attenuating PA stiffening, which provides insight into sex differences in PAH progression.

Sex Differences in Right Ventricular-Vascular Coupling and Pulmonary Artery Impedance in Response to Chronic Hypoxia and Recovery

2012 ◽  
Author(s):  
Aiping Liu ◽  
Lian Tian ◽  
Diana M. Tabima ◽  
Naomi C. Chesler
Keyword(s):  
Pulmonary Artery ◽  
Chronic Hypoxia ◽  
Pulmonary Arteries ◽  
Pulmonary Artery Hypertension ◽  
Vascular Impedance ◽  
Female Predominance ◽  
Collagen Accumulation ◽  
Dominant Disease ◽  
Pulmonary Arterial

Pulmonary artery hypertension (PAH) is a female dominant disease (the female-to-male ratio is 4:1), characterized by small distal pulmonary arterial narrowing and large proximal arterial stiffening, which increase right ventricle (RV) afterload and ultimately lead to RV failure [1,2]. Our recent studies have shown that collagen accumulation induced by chronic hypoxia increases the stiffness of the large extralobar pulmonary arteries (PAs) [3], and affects pulmonary vascular impedance (PVZ) [4]. The role of collagen in the female predominance in developing PAH has not been explored to date.

scholarly journals Pathobiology of pulmonary artery hypertension: role of long non-coding RNAs

2020 ◽  
Vol 116 (12) ◽  
pp. 1937-1947 ◽  
Author(s):  
Kashif Rafiq Zahid ◽  
Umar Raza ◽  
Jidong Chen ◽  
Usha J Raj ◽  
Deming Gou
Keyword(s):  
Pulmonary Artery ◽  
Right Ventricular Dysfunction ◽  
Pulmonary Artery Hypertension ◽  
Endothelial Cell Proliferation ◽  
Vascular Remodelling ◽  
Mesenchymal Transition ◽  
Pulmonary Arterial ◽  
Non Coding Rnas

Abstract Pulmonary arterial hypertension (PAH) is a disease with complex pathobiology, significant morbidity and mortality, and remains without a cure. It is characterized by vascular remodelling associated with uncontrolled proliferation of pulmonary artery smooth muscle cells, endothelial cell proliferation and dysfunction, and endothelial-to-mesenchymal transition, leading to narrowing of the vascular lumen, increased vascular resistance and pulmonary arterial pressure, which inevitably results in right heart failure and death. There are multiple molecules and signalling pathways that are involved in the vascular remodelling, including non-coding RNAs, i.e. microRNAs and long non-coding RNAs (lncRNAs). It is only in recent years that the role of lncRNAs in the pathobiology of pulmonary vascular remodelling and right ventricular dysfunction is being vigorously investigated. In this review, we have summarized the current state of knowledge about the role of lncRNAs as key drivers and gatekeepers in regulating major cellular and molecular trafficking involved in the pathogenesis of PAH. In addition, we have discussed the limitations and challenges in translating lncRNA research in vivo and in therapeutic applications of lncRNAs in PAH.

ID: 123: ROLE OF MICRORNA-1 IN REGULATING PULMONARY VASCULAR REMODELING IN PULMONARY ARTERIAL HYPERTENSION

2016 ◽  
Vol 64 (4) ◽  
pp. 969.1-969 ◽  
Author(s):  
JR Sysol ◽  
J Chen ◽  
S Singla ◽  
V Natarajan ◽  
RF Machado ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Luciferase Reporter ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle

RationalePulmonary arterial hypertension (PAH) is a severe, progressive disease characterized by increased pulmonary arterial pressure and resistance due in part to uncontrolled vascular remodeling. The mechanisms contributing to vascular remodeling in PAH are poorly understood and involve rampant pulmonary artery smooth muscle cell (PASMC) proliferation. We recently demonstrated the important role of sphingosine kinase 1 (SphK1), a lipid kinase producing pro-proliferative sphingosine-1-phosphate (S1P), in the development of pulmonary vascular remodeling in PAH. However, the regulatory processes involved in upregulation of SphK1 in this disease are unknown.ObjectiveIn this study, we aimed to identify novel molecular mechanisms governing the regulation of SphK1 expression, with a focus on microRNA (miR). Using both in vitro studies in pulmonary artery smooth muscle cells (PASMCs) and an in vivo mouse model of experimental hypoxia-mediated pulmonary hypertension (HPH), we explored the role of miR in controlling SphK1 expression in the development of pulmonary vascular remodeling.Methods and ResultsIn silico analysis identified hsa-miR-1-3p (miR-1) as a candidate targeting SphK1. We demonstrate miR-1 is down-regulated by hypoxia in human PASMCs and in lung tissues of mice with HPH, coinciding with upregulation of SphK1 expression. PASMCs isolated from patients with PAH had significantly reduced expression of miR-1. Transfection of human PASMCs with miR-1 mimics significantly attenuated activity of a SphK1-3'-UTR luciferase reporter construct and SphK1 protein expression. miR-1 overexpression in human PASMCs also inhibited proliferation and migration under normoxic and hypoxic conditions, both important in pathogenic vascular remodeling in PAH. Finally, we demonstrated that intravenous administration of miR-1 mimics prevents the development of experimental HPH in mice and attenuates induction of SphK1 in PASMCs.ConclusionThese data demonstrate that miR-1 expression in reduced in PASMCs from PAH patients, is modulated by hypoxia, and regulates the expression of SphK1. Key phenotypic aspects of vascular remodeling are influenced by miR-1 and its overexpression can prevent the development of HPH in mice. These studies further our understanding of the mechanisms underlying pathogenic pulmonary vascular remodeling in PAH and could lead to novel therapeutic targets.Supported by grants NIH/NHLBI R01 HL127342 and R01 HL111656 to RFM, NIH/NHLBI P01 HL98050 and R01 HL127342 to VN, American Heart Association Predoctoral Fellowship (15PRE2190004) to JRS, and NIH/NLHBI NRSA F30 Fellowship (FHL128034A) to JRS.

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 MiR-193-3p attenuates the vascular remodeling in pulmonary arterial hypertension by targeting PAK4

2020 ◽  
Vol 10 (4) ◽  
pp. 204589402097491
Author(s):  
Zhenhua Wu ◽  
Jie Geng ◽  
Yujuan Qi ◽  
Jian Li ◽  
Yaobang Bai ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Luciferase Reporter ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease associated with dysfunction of pulmonary artery endothelial cells and pulmonary artery smooth muscle cells (PASMCs). To explore the potential mechanism of miR-193-3p in pulmonary arterial hypertension, human PASMCs and rats were respectively stimulated by hypoxia and monocrotaline to establish PAH model in vivo and in vitro. The expressions of miR-193-3p and p21-activated protein kinase 4 (PAK4) in the lung samples of PAH patients and paired healthy samples from the healthy subjects in PHA cells and rats were detected by quantitative reverse transcriptase-PCR. Morphological changes in lung tissues were determined using hematoxylin and eosin staining. Right ventricular systolic pressure (RVSP) and ratio of right ventricle to left ventricle plus septum (RV/LV p S) were measured. The binding relationship between miR-193-3p and PAK4 was analyzed by TargetScan and verified by luciferase reporter assay. Cell viability, apoptosis, and migration were detected by 3-(4, 5-Dimethylthiazol-2- yl)-2,5-diphenyltetrazolium bromide (MTT) flow cytometry, and wound-healing assays, respectively. The protein expressions of PAK4, proliferating cell nuclear antigen (PCNA), P21, p-AKT, and AKT in vivo or in vitro were determined by Western blot. In this study, we found that in pulmonary arterial hypertension, miR-193-3p expression was downregulated and PAK4 expression was up-regulated. MiR-193-3p directly targeted PAK4 and negatively regulated its expression. Hypoxia condition promoted cell proliferation, migration, and inhibited apoptosis accompanied with increased expressions of PCNA and p-AKT/AKT and decreased expression of P21 in PASMCs. MiR-193-3p overexpression attenuated the effects of hypoxia on PASMCs via downregulating PAK4. Monocrotaline treatment increased p-AKT/AKT and decreased P21 expression and caused pulmonary vascular remodeling in the model rats. MiR-193-3p overexpression attenuated pulmonary vascular remodeling, decreased p-AKT/AKT, and increased P21 levels via downregulating PAK4 in monocrotaline-induced rats. The results in this study demonstrated that upregulation of miR-193-3p reduced cell proliferation, migration, and apoptosis of PAH in vitro and pulmonary vascular remodeling in PAH in vivo through downregulating PAK4.

scholarly journals Emerging Role of Galectin-3 in Pulmonary Artery Hypertension

2018 ◽  
Vol 1 (1) ◽  
pp. p35
Author(s):  
Alexander E. Berezin
Keyword(s):  
Heart Failure ◽  
Cell Proliferation ◽  
Pulmonary Artery ◽  
Short Communication ◽  
Clinical Status ◽  
Pulmonary Artery Hypertension ◽  
All Cause Mortality ◽  
Galectin 3 ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is multifactorial disadptive disease with poor clinical outcomes associated with increased pulmonary artery pressure resulting in primary small-to-moderate pulmonary artery remodeling. Numerous factors, including smooth muscle cell proliferation, vasospasm, vascular fibrosis and occlusion, direct vascular injury and inflammation, impaired repair of vasculature, are involved in the pathogenesis of PAH. It has been suggested that galectin-3 as a biomarker of excessive fibrosis and inflammation can be useful predictor of both severity and prognosis in patient with PAH. The short communication is reported that elevated Gal-3 levels were found in majority patients with PAH depending on clinical status and of the disease. Although elevated Gal-3 levels were associated with a higher risk of all-cause mortality, cardiovascular mortality, and right ventricle heart failure, the value of this biomarker in PAH patients at high risk stratification is uncertain and requires to be investigated in large clinical trials.

scholarly journals Upregulation of SIRT1 and FOXO3a Contributes to The Protective Role of Estrogen on HPH in Rats

2020 ◽  
Author(s):  
Li Wang ◽  
Yadong Yuan ◽  
Xiaowei Gong ◽  
Jianjun Mao
Keyword(s):  
Pulmonary Artery ◽  
Protective Role ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Pulmonary Vascular Remodeling ◽  
Sprague Dawley Rats ◽  
Sirt1 Activator

Abstract Background: SIRT1 has anti-proliferation effects on cells through regulating the expression and activity of FOXOs. Estrogen (E2) has protective effects against hypoxic pulmonary hypertension (HPH), but the involvement of SIRT1 and FOXOs in the proliferation of pulmonary artery smooth muscle cells (PASMCs) and contribution to the effects of E2 on HPH are poorly understood. To use E2 to explore the roles of SIRT1 and FOXO3a in the pathogenesis and progression of HPH and pulmonary vascular remodeling (PVR) in vivo and in vitro.Methods: Female Sprague-Dawley rats with bilateral ovariectomy were randomized to normoxia, normoxia+E2, hypoxia, and hypoxia+E2. Serum E2 levels, hemodynamic, and pulmonary vascular pathomorphology were assessed. The anti-proliferation effect of E2 was determined in human PASMCs under hypoxia/normoxia. Immunohistochemistry, western blotting, and real-time PCR were used to assess SIRT1, FOXO3a, and PCNA in rat pulmonary artery and hPASMCs. SIRT1 activity was assayed.Results: Hypoxia increased mean pulmonary artery pressure (mPAP), medial width of pulmonary arterioles, right ventricular hypertrophy index (RVHI), decreased expression SIRT1 and FOXO3a and increased PCNA expression in rats; E2 alleviated these changes. In vitro, E2 significantly inhibited hypoxia-induced hPASMCs proliferation, associated with improvements in SIRT1 and FOXO3a expression, consistent with the in vivo results. SIRT1 inhibition attenuated the effects of E2 on hPASMCs proliferation and the expression of FOXO3a. A SIRT1 activator mimicked the effects of E2 on hPASMCs proliferation and the expression of FOXO3a.Conclusions: Upregulation of SIRT1 and FOXO3a contributes to the protective role of estrogen on HPH in rats, as supported by in vitro results using hPASMCs.

scholarly journals Role of interleukins in the pathogenesis of pulmonary fibrosis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yi Xin She ◽  
Qing Yang Yu ◽  
Xiao Xiao Tang
Keyword(s):  
Pulmonary Fibrosis ◽  
Therapeutic Strategy ◽  
Future Directions ◽  
Regulation Mechanisms ◽  
Underlying Mechanisms ◽  
Multiple Cells ◽  
The Relationship

AbstractInterleukins, a group of cytokines participating in inflammation and immune response, are proved to be involved in the formation and development of pulmonary fibrosis. In this article, we reviewed the relationship between interleukins and pulmonary fibrosis from the clinical, animal, as well as cellular levels, and discussed the underlying mechanisms in vivo and in vitro. Despite the effects of interleukin-targeted treatment on experimental pulmonary fibrosis, clinical applications are lacking and unsatisfactory. We conclude that intervening in one type of interleukins with similar functions in IPF may not be enough to stop the development of fibrosis as it involves a complex network of regulation mechanisms. Intervening interleukins combined with other existing therapy or targeting interleukins affecting multiple cells/with different functions at the same time may be one of the future directions. Furthermore, the intervention time is critical as some interleukins play different roles at different stages. Further elucidation on these aspects would provide new perspectives on both the pathogenesis mechanism, as well as the therapeutic strategy and drug development.

scholarly journals EXPRESS: Pulmonary Hypertension Associated With Neurofibromatosis Type 2

2021 ◽  
pp. 204589402110295
Author(s):  
Hirohisa Taniguchi ◽  
Tomoya Takashima ◽  
Ly Tu ◽  
Raphaël Thuillet ◽  
Asuka Furukawa ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Neurofibromatosis Type ◽  
Pulmonary Vascular Remodeling ◽  
Life Threatening ◽  
History Of ◽  
Pulmonary Arterial ◽  
First Time

Although precapillary pulmonary hypertension (PH) is a rare but severe complication of patients with neurofibromatosis type 1 (NF1), its association with NF2 remains unknown. Herein, we report a case of a 44-year-old woman who was initially diagnosed with idiopathic pulmonary arterial hypertension (IPAH) and treated with PAH-specific combination therapy. However, a careful assessment for a relevant family history of the disease and genetic testing reveal that this patient had a mutation in the NF2 gene. Using immunofluorescence and Western blotting, we demonstrated a decrease in endothelial NF2 protein in lungs from IPAH patients compared to control lungs, suggesting a potential role of NF2 in PAH development. To our knowledge, this is the first time that precapillary PH has been described in a patient with NF2. The altered endothelial NF2 expression pattern in PAH lungs should stimulate work to better understand how NF2 is contributing to the pulmonary vascular remodeling associated to these severe life-threatening conditions.

scholarly journals Endothelial cell-related autophagic pathways in Sugen/hypoxia-exposed pulmonary arterial hypertensive rats

2017 ◽  
Vol 313 (5) ◽  
pp. L899-L915 ◽  
Author(s):  
Fumiaki Kato ◽  
Seiichiro Sakao ◽  
Takao Takeuchi ◽  
Toshio Suzuki ◽  
Rintaro Nishimura ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Endothelial Cell ◽  
Vascular Remodeling ◽  
Time Dependent ◽  
Causative Role ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is characterized by progressive obstructive remodeling of pulmonary arteries. However, no reports have described the causative role of the autophagic pathway in pulmonary vascular endothelial cell (EC) alterations associated with PAH. This study investigated the time-dependent role of the autophagic pathway in pulmonary vascular ECs and pulmonary vascular EC kinesis in a severe PAH rat model (Sugen/hypoxia rat) and evaluated whether timely induction of the autophagic pathway by rapamycin improves PAH. Hemodynamic and histological examinations as well as flow cytometry of pulmonary vascular EC-related autophagic pathways and pulmonary vascular EC kinetics in lung cell suspensions were performed. The time-dependent and therapeutic effects of rapamycin on the autophagic pathway were also assessed. Sugen/hypoxia rats treated with the vascular endothelial growth factor receptor blocker SU5416 showed increased right ventricular systolic pressure (RVSP) and numbers of obstructive vessels due to increased pulmonary vascular remodeling. The expression of the autophagic marker LC3 in ECs also changed in a time-dependent manner, in parallel with proliferation and apoptotic markers as assessed by flow cytometry. These results suggest the presence of cross talk between pulmonary vascular remodeling and the autophagic pathway, especially in small vascular lesions. Moreover, treatment of Sugen/hypoxia rats with rapamycin after SU5416 injection activated the autophagic pathway and improved the balance between cell proliferation and apoptosis in pulmonary vascular ECs to reduce RVSP and pulmonary vascular remodeling. These results suggested that the autophagic pathway can suppress PAH progression and that rapamycin-dependent activation of the autophagic pathway could ameliorate PAH.

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