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Cells
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Pulmonary Vascular Remodeling: Cellular and Molecular Mechanisms
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Pulmonary Vascular Remodeling: Cellular and Molecular Mechanisms

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Cardiovascular System".

Deadline for manuscript submissions: closed (15 July 2020) | Viewed by 26002

Special Issue Editor

Dr. Leigh Marsh

E-Mail Website
Guest Editor
Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
Interests: chronic lung disease; immunity; pulmonary hypertension; computational flow cytometry

Special Issue Information

Dear Colleagues,

Pulmonary hypertension (PH) can manifest in its standalone idiopathic form or be associated with chronic lung disease, where even a mild elevation of pulmonary arterial pressure is associated with poor prognosis. All forms of PH possess pathologial remodeling of the pulmonary vessels, sharing common characteristics such as medial hypertrophy and intimal thickening. The current consensus is that vascular remodeling arises from a dysfunctional endothelium and the perturbed crosstalk between other resident structural cell types, including pericytes, smooth muscle cells, and fibroblasts. Recruited inflammatory cells can actively affect remodeling by releasing potent signaling molecules such as growth factors, cytokines, and enzymes and thereby alter vascular homeostasis. However, many of the mechansims that govern cell accumulation or mediate cellular cross-talk are still unidentified. Therefore, delineating this cross-talk and communication between diverse cell types and involved signaling processess is crucial to better understanding remodeling and bring us towards more targeted therapies, which can be specifically applied in different forms of PH. This Special Issue focuses on multiple aspects that govern vascular remodeling, and especially the interaction between different resident cell types and immune cells.

Dr. Leigh Marsh
Guest Editor

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.

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • remodeling
  • crosstalk
  • inflammation
  • extracellular matrix
  • signaling
  • signal transduction
  • vessels
  • pulmonary
  • hypertension
  • remodeling

Published Papers (6 papers)

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Research

Jump to: Review

11 pages, 1716 KiB  
Article
The Inflammatory Profile of CTEPH-Derived Endothelial Cells Is a Possible Driver of Disease Progression
by Valérie F. E. D. Smolders, Kirsten Lodder, Cristina Rodríguez, Olga Tura-Ceide, Joan Albert Barberà, J. Wouter Jukema, Paul H. A. Quax, Marie José Goumans and Kondababu Kurakula
Cells 2021, 10(4), 737; https://doi.org/10.3390/cells10040737 - 26 Mar 2021
Cited by 15 | Viewed by 2644
Abstract
Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary hypertension characterized by the presence of fibrotic intraluminal thrombi and causing obliteration of the pulmonary arteries. Although both endothelial cell (EC) dysfunction and inflammation are linked to CTEPH pathogenesis, regulation of the basal [...] Read more.
Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary hypertension characterized by the presence of fibrotic intraluminal thrombi and causing obliteration of the pulmonary arteries. Although both endothelial cell (EC) dysfunction and inflammation are linked to CTEPH pathogenesis, regulation of the basal inflammatory response of ECs in CTEPH is not fully understood. Therefore, in the present study, we investigated the role of the nuclear factor (NF)-κB pro-inflammatory signaling pathway in ECs in CTEPH under basal conditions. Basal mRNA levels of interleukin (IL)-8, IL-1β, monocyte chemoattractant protein-1 (MCP-1), C-C motif chemokine ligand 5 (CCL5), and vascular cell adhesion molecule-1 (VCAM-1) were upregulated in CTEPH-ECs compared to the control cells. To assess the involvement of NF-κB signaling in basal inflammatory activation, CTEPH-ECs were incubated with the NF-κB inhibitor Bay 11-7085. The increase in pro-inflammatory cytokines was abolished when cells were incubated with the NF-κB inhibitor. To determine if NF-κB was indeed activated, we stained pulmonary endarterectomy (PEA) specimens from CTEPH patients and ECs isolated from PEA specimens for phospho-NF-κB-P65 and found that especially the vessels within the thrombus and CTEPH-ECs are positive for phospho-NF-κB-P65. In summary, we show that CTEPH-ECs have a pro-inflammatory status under basal conditions, and blocking NF-κB signaling reduces the production of inflammatory factors in CTEPH-ECs. Therefore, our results show that the increased basal pro-inflammatory status of CTEPH-ECs is, at least partially, regulated through activation of NF-κB signaling and potentially contributes to the pathophysiology and progression of CTEPH. Full article
(This article belongs to the Special Issue Pulmonary Vascular Remodeling: Cellular and Molecular Mechanisms)
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13 pages, 2780 KiB  
Article
Altered TGFβ/SMAD Signaling in Human and Rat Models of Pulmonary Hypertension: An Old Target Needs Attention
by Takayuki Jujo Sanada, Xiao-Qing Sun, Chris Happé, Christophe Guignabert, Ly Tu, Ingrid Schalij, Harm-Jan Bogaard, Marie-José Goumans and Kondababu Kurakula
Cells 2021, 10(1), 84; https://doi.org/10.3390/cells10010084 - 6 Jan 2021
Cited by 16 | Viewed by 3581
Abstract
Recent translational studies highlighted the inhibition of transforming growth factor (TGF)-β signaling as a promising target to treat pulmonary arterial hypertension (PAH). However, it remains unclear whether alterations in TGF-β signaling are consistent between PAH patients and animal models. Therefore, we compared TGF-β [...] Read more.
Recent translational studies highlighted the inhibition of transforming growth factor (TGF)-β signaling as a promising target to treat pulmonary arterial hypertension (PAH). However, it remains unclear whether alterations in TGF-β signaling are consistent between PAH patients and animal models. Therefore, we compared TGF-β signaling in the lungs of PAH patients and rats with experimental PAH induced by monocrotaline (MCT) or SU5416+hypoxia (SuHx). In hereditary PAH (hPAH) patients, there was a moderate increase in both TGFβR2 and pSMAD2/3 protein levels, while these were unaltered in idiopathic PAH (iPAH) patients. Protein levels of TGFβR2 and pSMAD2/3 were locally increased in the pulmonary vasculature of PAH rats under both experimental conditions. Conversely, the protein levels of TGFβR2 and pSMAD2/3 were reduced in SuHx while slightly increased in MCT. mRNA levels of plasminogen activator inhibitor (PAI)-1 were increased only in MCT animals and such an increase was not observed in SuHx rats or in iPAH and hPAH patients. In conclusion, our data demonstrate considerable discrepancies in TGFβ-SMAD signaling between iPAH and hPAH patients, as well as between patients and rats with experimental PAH. Full article
(This article belongs to the Special Issue Pulmonary Vascular Remodeling: Cellular and Molecular Mechanisms)
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14 pages, 2517 KiB  
Article
IRAG1 Deficient Mice Develop PKG1β Dependent Pulmonary Hypertension
by Siladitta Biswas, Baktybek Kojonazarov, Stefan Hadzic, Michael Majer, Ganimete Bajraktari, Tatyana Novoyatleva, Hossein Ardeschir Ghofrani, Friedrich Grimminger, Werner Seeger, Norbert Weissmann, Jens Schlossmann and Ralph Theo Schermuly
Cells 2020, 9(10), 2280; https://doi.org/10.3390/cells9102280 - 13 Oct 2020
Cited by 5 | Viewed by 2691
Abstract
PKGs are serine/threonine kinases. PKG1 has two isoforms—PKG1α and β. Inositol trisphosphate receptor (IP3R)-associated cGMP-kinase substrate 1 (IRAG1) is a substrate for PKG1β. IRAG1 is also known to further interact with IP3RI, which mediates intracellular Ca2+ release. However, [...] Read more.
PKGs are serine/threonine kinases. PKG1 has two isoforms—PKG1α and β. Inositol trisphosphate receptor (IP3R)-associated cGMP-kinase substrate 1 (IRAG1) is a substrate for PKG1β. IRAG1 is also known to further interact with IP3RI, which mediates intracellular Ca2+ release. However, the role of IRAG1 in PH is not known. Herein, WT and IRAG1 KO mice were kept under normoxic or hypoxic (10% O2) conditions for five weeks. Animals were evaluated for echocardiographic variables and went through right heart catheterization. Animals were further sacrificed to prepare lungs and right ventricular (RV) for immunostaining, western blotting, and pulmonary artery smooth muscle cell (PASMC) isolation. IRAG1 is expressed in PASMCs and downregulated under hypoxic conditions. Genetic deletion of IRAG1 leads to RV hypertrophy, increase in RV systolic pressure, and RV dysfunction in mice. Absence of IRAG1 in lung and RV have direct impacts on PKG1β expression. Attenuated PKG1β expression in IRAG1 KO mice further dysregulates other downstream candidates of PKG1β in RV. IRAG1 KO mice develop PH spontaneously. Our results indicate that PKG1β signaling via IRAG1 is essential for the homeostasis of PASMCs and RV. Disturbing this signaling complex by deleting IRAG1 can lead to RV dysfunction and development of PH in mice. Full article
(This article belongs to the Special Issue Pulmonary Vascular Remodeling: Cellular and Molecular Mechanisms)
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25 pages, 11282 KiB  
Article
Endothelial Dysfunction Following Enhanced TMEM16A Activity in Human Pulmonary Arteries
by Davor Skofic Maurer, Diana Zabini, Chandran Nagaraj, Neha Sharma, Miklós Lengyel, Bence M. Nagy, Saša Frank, Walter Klepetko, Elisabeth Gschwandtner, Péter Enyedi, Grazyna Kwapiszewska, Horst Olschewski and Andrea Olschewski
Cells 2020, 9(9), 1984; https://doi.org/10.3390/cells9091984 - 28 Aug 2020
Cited by 18 | Viewed by 3151
Abstract
Endothelial dysfunction is one of the hallmarks of different vascular diseases, including pulmonary arterial hypertension (PAH). Ion channelome changes have long been connected to vascular remodeling in PAH, yet only recently has the focus shifted towards Ca2+-activated Cl− channels (CaCC). [...] Read more.
Endothelial dysfunction is one of the hallmarks of different vascular diseases, including pulmonary arterial hypertension (PAH). Ion channelome changes have long been connected to vascular remodeling in PAH, yet only recently has the focus shifted towards Ca2+-activated Cl− channels (CaCC). The most prominent member of the CaCC TMEM16A has been shown to contribute to the pathogenesis of idiopathic PAH (IPAH) in pulmonary arterial smooth muscle cells, however its role in the homeostasis of healthy human pulmonary arterial endothelial cells (PAECs) and in the development of endothelial dysfunction remains underrepresented. Here we report enhanced TMEM16A activity in IPAH PAECs by whole-cell patch-clamp recordings. Using adenoviral-mediated TMEM16A increase in healthy primary human PAECs in vitro and in human pulmonary arteries ex vivo, we demonstrate the functional consequences of the augmented TMEM16A activity: alterations of Ca2+ dynamics and eNOS activity as well as decreased NO production, PAECs proliferation, wound healing, tube formation and acetylcholine-mediated relaxation of human pulmonary arteries. We propose that the ERK1/2 pathway is specifically affected by elevated TMEM16A activity, leading to these pathological changes. With this work we introduce increased TMEM16A activity in the cell membrane of human PAECs for the development of endothelial dysfunction in PAH. Full article
(This article belongs to the Special Issue Pulmonary Vascular Remodeling: Cellular and Molecular Mechanisms)
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Review

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25 pages, 1995 KiB  
Review
Perivascular Inflammation in Pulmonary Arterial Hypertension
by Yijie Hu, Leon Chi, Wolfgang M Kuebler and Neil M Goldenberg
Cells 2020, 9(11), 2338; https://doi.org/10.3390/cells9112338 - 22 Oct 2020
Cited by 104 | Viewed by 8963
Abstract
Perivascular inflammation is a prominent pathologic feature in most animal models of pulmonary hypertension (PH) as well as in pulmonary arterial hypertension (PAH) patients. Accumulating evidence suggests a functional role of perivascular inflammation in the initiation and/or progression of PAH and pulmonary vascular [...] Read more.
Perivascular inflammation is a prominent pathologic feature in most animal models of pulmonary hypertension (PH) as well as in pulmonary arterial hypertension (PAH) patients. Accumulating evidence suggests a functional role of perivascular inflammation in the initiation and/or progression of PAH and pulmonary vascular remodeling. High levels of cytokines, chemokines, and inflammatory mediators can be detected in PAH patients and correlate with clinical outcome. Similarly, multiple immune cells, including neutrophils, macrophages, dendritic cells, mast cells, T lymphocytes, and B lymphocytes characteristically accumulate around pulmonary vessels in PAH. Concomitantly, vascular and parenchymal cells including endothelial cells, smooth muscle cells, and fibroblasts change their phenotype, resulting in altered sensitivity to inflammatory triggers and their enhanced capacity to stage inflammatory responses themselves, as well as the active secretion of cytokines and chemokines. The growing recognition of the interaction between inflammatory cells, vascular cells, and inflammatory mediators may provide important clues for the development of novel, safe, and effective immunotargeted therapies in PAH. Full article
(This article belongs to the Special Issue Pulmonary Vascular Remodeling: Cellular and Molecular Mechanisms)
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25 pages, 1164 KiB  
Review
Endothelial Basement Membrane Components and Their Products, Matrikines: Active Drivers of Pulmonary Hypertension?
by Ayse Ceren Mutgan, Katharina Jandl and Grazyna Kwapiszewska
Cells 2020, 9(9), 2029; https://doi.org/10.3390/cells9092029 - 3 Sep 2020
Cited by 26 | Viewed by 4333
Abstract
Pulmonary arterial hypertension (PAH) is a vascular disease that is characterized by elevated pulmonary arterial pressure (PAP) due to progressive vascular remodeling. Extracellular matrix (ECM) deposition in pulmonary arteries (PA) is one of the key features of vascular remodeling. Emerging evidence indicates that [...] Read more.
Pulmonary arterial hypertension (PAH) is a vascular disease that is characterized by elevated pulmonary arterial pressure (PAP) due to progressive vascular remodeling. Extracellular matrix (ECM) deposition in pulmonary arteries (PA) is one of the key features of vascular remodeling. Emerging evidence indicates that the basement membrane (BM), a specialized cluster of ECM proteins underlying the endothelium, may be actively involved in the progression of vascular remodeling. The BM and its steady turnover are pivotal for maintaining appropriate vascular functions. However, the pathologically elevated turnover of BM components leads to an increased release of biologically active short fragments, which are called matrikines. Both BM components and their matrikines can interfere with pivotal biological processes, such as survival, proliferation, adhesion, and migration and thus may actively contribute to endothelial dysfunction. Therefore, in this review, we summarize the emerging role of the BM and its matrikines on the vascular endothelium and further discuss its implications on lung vascular remodeling in pulmonary hypertension. Full article
(This article belongs to the Special Issue Pulmonary Vascular Remodeling: Cellular and Molecular Mechanisms)
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