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Molecular Mechanisms and Pathophysiology of Pulmonary Vascular Remodeling
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Molecular Mechanisms and Pathophysiology of Pulmonary Vascular Remodeling

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (28 April 2022) | Viewed by 14701

Special Issue Editors

Prof. Dr. Andrea Olschewski

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Guest Editor
Department of Anaesthesiology and Intensive Care Medicine, Medical University of Graz, 8036 Graz, Austria
Interests: potassium and chloride channels; ion channels-related pulmonary diseases; pulmonary vascular physiology; vascular smooth muscle physiology and pathophysiology, endothelial dysfunction
Dr. Valentina Biasin

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Guest Editor
Divison of Endocrinology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
Interests: transcriptional factors; fra-2, lung fibrosis; steroid hormones
Dr. Chandran Nagaraj

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Guest Editor
Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
Interests: ion channels; pulmonary vascular remodeling; endothelial dysfunction
Dr. Bence Nagy

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Guest Editor
Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
Interests: metabolomics; ABC transporters; mitochondria

Special Issue Information

Dear Colleagues,

Excessive remodeling of the normally low-pressure pulmonary vasculature is a common multifactorial pathological process resulting in elevated pulmonary vascular resistance and pulmonary hypertension (PH). The World Symposium on Pulmonary Hypertension classifies five categories of PH, including pulmonary arterial hypertension (PAH), PH secondary to left heart disease (Group 2), PH due to chronic lung disease and/or hypoxia (Group 3) thromboembolic disease (Group 4), or PH due to unclear or multifactorial mechanisms (Group 5). All these groups have distinct pathological mechanisms and different molecular mechanisms may even be dominant within groups. A broad range of dysregulation of essential pathways inside and outside of the lung has been discovered. Although the understanding of PH pathobiology has increased substantially over recent years, many molecular and cellular mechanisms have not been identified or fully understood.

This Special Issue is dedicated to molecular mechanisms and pathophysiology of pulmonary vascular remodeling. Research articles and reviews will inform you about recent developments and update the current stage of knowledge.

Prof. Dr. Andrea Olschewski
Dr. Chandran Nagaraj
Dr. Valentina Biasin
Dr. Bence Nagy
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Vascular inflammation
  • Channelopathies
  • Innate and adaptive immune system
  • Metabolic stress
  • Mitochondrial dysfunction
  • Epigenetic rewiring
  • Growth factor signaling
  • Vascular remodeling
  • Transcriptional factors
  • Sexual dimorphism
  • Endothelial dysfunction
  •  Vascular smooth muscle
  •  Translational approach

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Published Papers (3 papers)

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Research

20 pages, 5011 KiB  
Article
The Short-Chain Fatty Acid Butyrate Attenuates Pulmonary Vascular Remodeling and Inflammation in Hypoxia-Induced Pulmonary Hypertension
by Vijaya Karoor, Derek Strassheim, Timothy Sullivan, Alexander Verin, Nagavedi S. Umapathy, Edward C. Dempsey, Daniel N. Frank, Kurt R. Stenmark and Evgenia Gerasimovskaya
Int. J. Mol. Sci. 2021, 22(18), 9916; https://doi.org/10.3390/ijms22189916 - 14 Sep 2021
Cited by 39 | Viewed by 6071
Abstract
Pulmonary hypertension (PH) is a progressive cardiovascular disorder in which local vascular inflammation leads to increased pulmonary vascular remodeling and ultimately to right heart failure. The HDAC inhibitor butyrate, a product of microbial fermentation, is protective in inflammatory intestinal diseases, but little is [...] Read more.
Pulmonary hypertension (PH) is a progressive cardiovascular disorder in which local vascular inflammation leads to increased pulmonary vascular remodeling and ultimately to right heart failure. The HDAC inhibitor butyrate, a product of microbial fermentation, is protective in inflammatory intestinal diseases, but little is known regarding its effect on extraintestinal diseases, such as PH. In this study, we tested the hypothesis that butyrate is protective in a Sprague–Dawley (SD) rat model of hypoxic PH. Treatment with butyrate (220 mg/kg intake) prevented hypoxia-induced right ventricular hypertrophy (RVH), hypoxia-induced increases in right ventricular systolic pressure (RVSP), pulmonary vascular remodeling, and permeability. A reversal effect of butyrate (2200 mg/kg intake) was observed on elevated RVH. Butyrate treatment also increased the acetylation of histone H3, 25–34 kDa, and 34–50 kDa proteins in the total lung lysates of butyrate-treated animals. In addition, butyrate decreased hypoxia-induced accumulation of alveolar (mostly CD68+) and interstitial (CD68+ and CD163+) lung macrophages. Analysis of cytokine profiles in lung tissue lysates showed a hypoxia-induced upregulation of TIMP-1, CINC-1, and Fractalkine and downregulation of soluble ICAM (sICAM). The expression of Fractalkine and VEGFα, but not CINC-1, TIMP-1, and sICAM was downregulated by butyrate. In rat microvascular endothelial cells (RMVEC), butyrate (1 mM, 2 and 24 h) exhibited a protective effect against TNFα- and LPS-induced barrier disruption. Butyrate (1 mM, 24 h) also upregulated tight junctional proteins (occludin, cingulin, claudin-1) and increased the acetylation of histone H3 but not α-tubulin. These findings provide evidence of the protective effect of butyrate on hypoxic PH and suggest its potential use as a complementary treatment for PH and other cardiovascular diseases. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Pulmonary Vascular Remodeling)
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16 pages, 2749 KiB  
Article
CDC2 Is an Important Driver of Vascular Smooth Muscle Cell Proliferation via FOXM1 and PLK1 in Pulmonary Arterial Hypertension
by Ruma Pal-Ghosh, Danfeng Xue, Rod Warburton, Nicholas Hill, Peter Polgar and Jamie L. Wilson
Int. J. Mol. Sci. 2021, 22(13), 6943; https://doi.org/10.3390/ijms22136943 - 28 Jun 2021
Cited by 8 | Viewed by 4270
Abstract
A key feature of pulmonary arterial hypertension (PAH) is the hyperplastic proliferation exhibited by the vascular smooth muscle cells from patients (HPASMC). The growth inducers FOXM1 and PLK1 are highly upregulated in these cells. The mechanism by which these two proteins direct aberrant [...] Read more.
A key feature of pulmonary arterial hypertension (PAH) is the hyperplastic proliferation exhibited by the vascular smooth muscle cells from patients (HPASMC). The growth inducers FOXM1 and PLK1 are highly upregulated in these cells. The mechanism by which these two proteins direct aberrant growth in these cells is not clear. Herein, we identify cyclin-dependent kinase 1 (CDK1), also termed cell division cycle protein 2 (CDC2), as having a primary role in promoting progress of the cell cycle leading to proliferation in HPASMC. HPASMC obtained from PAH patients and pulmonary arteries from Sugen/hypoxia rats were investigated for their expression of CDC2. Protein levels of CDC2 were much higher in PAH than in cells from normal donors. Knocking down FOXM1 or PLK1 protein expression with siRNA or pharmacological inhibitors lowered the cellular expression of CDC2 considerably. However, knockdown of CDC2 with siRNA or inhibiting its activity with RO-3306 did not reduce the protein expression of FOXM1 or PLK1. Expression of CDC2 and FOXM1 reached its maximum at G1/S, while PLK1 reached its maximum at G2/M phase of the cell cycle. The expression of other CDKs such as CDK2, CDK4, CDK6, CDK7, and CDK9 did not change in PAH HPASMC. Moreover, inhibition via Wee1 inhibitor adavosertib or siRNAs targeting Wee1, Myt1, CDC25A, CDC25B, or CDC25C led to dramatic decreases in CDC2 protein expression. Lastly, we found CDC2 expression at the RNA and protein level to be upregulated in pulmonary arteries during disease progression Sugen/hypoxia rats. In sum, our present results illustrate that the increased expression of FOXM1 and PLK1 in PAH leads directly to increased expression of CDC2 resulting in potentiated growth hyperactivity of PASMC from patients with pulmonary hypertension. Our results further suggest that the regulation of CDC2, or associated regulatory proteins, will prove beneficial in the treatment of this disease. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Pulmonary Vascular Remodeling)
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11 pages, 2909 KiB  
Article
Endothelial Autocrine Signaling through CXCL12/CXCR4/FoxM1 Axis Contributes to Severe Pulmonary Arterial Hypertension
by Dan Yi, Bin Liu, Ting Wang, Qi Liao, Maggie M. Zhu, You-Yang Zhao and Zhiyu Dai
Int. J. Mol. Sci. 2021, 22(6), 3182; https://doi.org/10.3390/ijms22063182 - 20 Mar 2021
Cited by 18 | Viewed by 3403
Abstract
Endothelial autocrine signaling is essential to maintain vascular homeostasis. There is limited information about the role of endothelial autocrine signaling in regulating severe pulmonary vascular remodeling during the onset of pulmonary arterial hypertension (PAH). In this study, we employed the first severe pulmonary [...] Read more.
Endothelial autocrine signaling is essential to maintain vascular homeostasis. There is limited information about the role of endothelial autocrine signaling in regulating severe pulmonary vascular remodeling during the onset of pulmonary arterial hypertension (PAH). In this study, we employed the first severe pulmonary hypertension (PH) mouse model, Egln1Tie2Cre (Tie2Cre-mediated disruption of Egln1) mice, to identify the novel autocrine signaling mediating the pulmonary vascular endothelial cell (PVEC) proliferation and the pathogenesis of PAH. PVECs isolated from Egln1Tie2Cre lung expressed upregulation of many growth factors or angiocrine factors such as CXCL12, and exhibited pro-proliferative phenotype coincident with the upregulation of proliferation-specific transcriptional factor FoxM1. Treatment of CXCL12 on PVECs increased FoxM1 expression, which was blocked by CXCL12 receptor CXCR4 antagonist AMD3100 in cultured human PVECs. The endothelial specific deletion of Cxcl12(Egln1/Cxcl12Tie2Cre) or AMD3100 treatment in Egln1Tie2Cre mice downregulated FoxM1 expression in vivo. We then generated and characterized a novel mouse model with endothelial specific FoxM1 deletion in Egln1Tie2Cre mice (Egln1/Foxm1Tie2Cre), and found that endothelial FoxM1 deletion reduced pulmonary vascular remodeling and right ventricular systolic pressure. Together, our study identified a novel mechanism of endothelial autocrine signaling in regulating PVEC proliferation and pulmonary vascular remodeling in PAH. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Pulmonary Vascular Remodeling)
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