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1
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Niihori M, James J, Varghese MV, McClain N, Lawal OS, Philip RC, Baggett BK, Goncharov DA, de Jesus Perez V, Goncharova EA, Rafikov R, Rafikova O. Mitochondria as a primary determinant of angiogenic modality in pulmonary arterial hypertension. J Exp Med 2024; 221:e20231568. [PMID: 39320470 PMCID: PMC11452743 DOI: 10.1084/jem.20231568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 03/27/2024] [Accepted: 08/19/2024] [Indexed: 09/26/2024] Open
Abstract
Impaired pulmonary angiogenesis plays a pivotal role in the progression of pulmonary arterial hypertension (PAH) and patient mortality, yet the molecular mechanisms driving this process remain enigmatic. Our study uncovered a striking connection between mitochondrial dysfunction (MD), caused by a humanized mutation in the NFU1 gene, and severely disrupted pulmonary angiogenesis in adult lungs. Restoring the bioavailability of the NFU1 downstream target, lipoic acid (LA), alleviated MD and angiogenic deficiency and rescued the progressive PAH phenotype in the NFU1G206C model. Notably, significant NFU1 expression and signaling insufficiencies were also identified in idiopathic PAH (iPAH) patients' lungs, emphasizing this study's relevance beyond NFU1 mutation cases. The remarkable improvement in mitochondrial function of PAH patient-derived pulmonary artery endothelial cells (PAECs) following LA supplementation introduces LA as a potential therapeutic approach. In conclusion, this study unveils a novel role for MD in dysregulated pulmonary angiogenesis and PAH manifestation, emphasizing the need to correct MD in PAH patients with unrecognized NFU1/LA deficiency.
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Affiliation(s)
- Maki Niihori
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University, Indianapolis, IN, USA
| | - Joel James
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University, Indianapolis, IN, USA
| | - Mathews V. Varghese
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University, Indianapolis, IN, USA
| | - Nolan McClain
- Department of Medicine, University of Arizona, Tucson, AZ, USA
| | - Odunayo Susan Lawal
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University, Indianapolis, IN, USA
| | - Rohit C. Philip
- Department of Electrical and Computer Engineering, University of Arizona College of Engineering, Tucson, AZ, USA
- Department of Medical Imaging, University of Arizona College of Medicine, Tucson, AZ, USA
| | - Brenda K. Baggett
- The University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA
| | - Dmitry A. Goncharov
- Division of Pulmonary, Critical Care and Sleep Medicine, Lung Center, University of California, Davis School of Medicine, Davis, CA, USA
| | - Vinicio de Jesus Perez
- Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, Stanford, CA, USA
| | - Elena A. Goncharova
- Division of Pulmonary, Critical Care and Sleep Medicine, Lung Center, University of California, Davis School of Medicine, Davis, CA, USA
| | - Ruslan Rafikov
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University, Indianapolis, IN, USA
| | - Olga Rafikova
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University, Indianapolis, IN, USA
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2
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Buschur KL, Pottinger TD, Vogel-Claussen J, Powell CA, Aguet F, Allen NB, Ardlie K, Bluemke DA, Durda P, Hermann EA, Hoffman EA, Lima JA, Liu Y, Malinsky D, Manichaikul A, Motahari A, Post WS, Prince MR, Rich SS, Rotter JI, Smith BM, Tracy RP, Watson K, Winther HB, Lappalainen T, Barr RG. Peripheral Blood Mononuclear Cell Gene Expression Associated with Pulmonary Microvascular Perfusion: The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease. Ann Am Thorac Soc 2024; 21:884-894. [PMID: 38335160 PMCID: PMC11160125 DOI: 10.1513/annalsats.202305-417oc] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 02/09/2024] [Indexed: 02/12/2024] Open
Abstract
Rationale: Chronic obstructive pulmonary disease (COPD) and emphysema are associated with endothelial damage and altered pulmonary microvascular perfusion. The molecular mechanisms underlying these changes are poorly understood in patients, in part because of the inaccessibility of the pulmonary vasculature. Peripheral blood mononuclear cells (PBMCs) interact with the pulmonary endothelium. Objectives: To test the association between gene expression in PBMCs and pulmonary microvascular perfusion in COPD. Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited two independent samples of COPD cases and controls with ⩾10 pack-years of smoking history. In both samples, pulmonary microvascular blood flow, pulmonary microvascular blood volume, and mean transit time were assessed on contrast-enhanced magnetic resonance imaging, and PBMC gene expression was assessed by microarray. Additional replication was performed in a third sample with pulmonary microvascular blood volume measures on contrast-enhanced dual-energy computed tomography. Differential expression analyses were adjusted for age, gender, race/ethnicity, educational attainment, height, weight, smoking status, and pack-years of smoking. Results: The 79 participants in the discovery sample had a mean age of 69 ± 6 years, 44% were female, 25% were non-White, 34% were current smokers, and 66% had COPD. There were large PBMC gene expression signatures associated with pulmonary microvascular perfusion traits, with several replicated in the replication sets with magnetic resonance imaging (n = 47) or dual-energy contrast-enhanced computed tomography (n = 157) measures. Many of the identified genes are involved in inflammatory processes, including nuclear factor-κB and chemokine signaling pathways. Conclusions: PBMC gene expression in nuclear factor-κB, inflammatory, and chemokine signaling pathways was associated with pulmonary microvascular perfusion in COPD, potentially offering new targetable candidates for novel therapies.
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Affiliation(s)
| | | | - Jens Vogel-Claussen
- Department of Diagnostic and Interventional Radiology, Hannover Medical School, Hannover, Germany
- Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | | | - Francois Aguet
- The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Norrina B. Allen
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Kristin Ardlie
- The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - David A. Bluemke
- Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Peter Durda
- Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, Vermont
| | | | - Eric A. Hoffman
- Department of Radiology, University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - João A.C. Lima
- Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, Maryland
| | - Yongmei Liu
- Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | | | - Ani Manichaikul
- Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia
| | - Amin Motahari
- Department of Radiology, University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Wendy S. Post
- Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, Maryland
| | | | - Stephen S. Rich
- Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia
| | - Jerome I. Rotter
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, California
| | - Benjamin M. Smith
- Department of Medicine
- Research Institute, McGill University Health Center, Montreal, Québec, Canada
| | - Russell P. Tracy
- Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, Vermont
| | - Karol Watson
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; and
| | - Hinrich B. Winther
- Department of Diagnostic and Interventional Radiology, Hannover Medical School, Hannover, Germany
| | - Tuuli Lappalainen
- Department of Biostatistics
- Department of Systems Biology, Columbia University Medical Center, New York, New York
- Science for Life Laboratory, Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden
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3
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Takada K, Suzukawa M, Igarashi S, Uehara Y, Watanabe S, Imoto S, Ishii M, Morio Y, Matsui H, Akishita M, Ohta K. Serum IgA augments adhesiveness of cultured lung microvascular endothelial cells and suppresses angiogenesis. Cell Immunol 2023; 393-394:104769. [PMID: 37741001 DOI: 10.1016/j.cellimm.2023.104769] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 09/11/2023] [Accepted: 09/15/2023] [Indexed: 09/25/2023]
Abstract
Immunoglobulin A (IgA) is important in local immunity and is also abundant in the blood. This study aimed to evaluate the effects of serum IgA on cultured lung microvascular endothelial cells (HMVEC-Ls), which are involved in the pathogenesis of inflammatory lung diseases. Serum IgA induced adhesion molecules and inflammatory cytokine production from HMVEC-Ls, and enhanced adhesion of peripheral blood mononuclear cells to HMVEC-Ls. In contrast, migration, proliferation, and tube formation of HMVEC-Ls were significantly suppressed by serum IgA. Experiments with siRNAs and western blotting revealed that two known IgA receptors, β1,4-galactosyltransferase 1 (b4GALT1) and asialoglycoprotein receptor 1 (ASGR1), and mitogen-activated protein kinase and nuclear factor-kappa B pathways were partly involved in serum IgA-induced cytokine production by HMVEC-Ls. Collectively, serum IgA enhanced cytokine production and adhesiveness of HMVEC-L, with b4GALT1 and ASGR1 partially being involved, and suppressed angiogenesis. Thus, serum IgA may be targeted to treat inflammatory lung diseases.
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Affiliation(s)
- Kazufumi Takada
- Clinical Research Center, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan; Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Maho Suzukawa
- Clinical Research Center, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan.
| | - Sayaka Igarashi
- Clinical Research Center, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan
| | - Yuuki Uehara
- Clinical Research Center, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan; Division of Respiratory Medicine and Allergology, Department of Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan
| | - Shizuka Watanabe
- Clinical Research Center, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan; Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Sahoko Imoto
- Clinical Research Center, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan; Division of Respiratory Medicine and Allergology, Department of Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan
| | - Masaki Ishii
- Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Yoshiteru Morio
- Department of Respiratory Medicine, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan
| | - Hirotoshi Matsui
- Department of Respiratory Medicine, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan
| | - Masahiro Akishita
- Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Ken Ohta
- Clinical Research Center, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan; Japan Anti-Tuberculosis Association, JATA Fukujuji Hospital, 3-1-24 Matsuyama, Kiyose-City, Tokyo 204-8522, Japan.
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4
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Kim JS, Lee EJ, Jeong HY, Jung KH. Chronic Lung Parenchymal Disease May Be Causally Associated With Cryptogenic Stroke With Massive Right-to-Left Shunt. J Stroke 2023; 25:413-416. [PMID: 37667457 PMCID: PMC10574306 DOI: 10.5853/jos.2023.01074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 06/28/2023] [Accepted: 08/08/2023] [Indexed: 09/06/2023] Open
Affiliation(s)
- Jong-Su Kim
- Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Eung-Joon Lee
- Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Han-Yeong Jeong
- Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Keun-Hwa Jung
- Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
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5
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Lee SJ, Jeong JH, Heo M, Ju S, Yoo JW, Jeong YY, Lee JD. Serum Fibrinogen as a Biomarker for Disease Severity and Exacerbation in Patients with Non-Cystic Fibrosis Bronchiectasis. J Clin Med 2022; 11:jcm11143948. [PMID: 35887712 PMCID: PMC9319061 DOI: 10.3390/jcm11143948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 06/28/2022] [Accepted: 07/01/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Serum biomarkers associated with severe non-cystic fibrosis (CF) bronchiectasis are currently lacking. We assessed the association of serum fibrinogen, adiponectin, and angiopoietin-2 levels with the severity and exacerbation of bronchiectasis. Methods: Serum levels of fibrinogen, adiponectin, and angiopoietin-2 were measured and compared in patients with stable non-CF bronchiectasis (n = 61) and healthy controls (n = 16). The correlations between the three biomarkers and the bronchiectasis severity index (BSI) or FACED scores were assessed. Univariate and multivariate linear regression analyses were performed to identify variables independently associated with BSI and FACED scores in patients with bronchiectasis. Additionally, the exacerbation-free survival was compared between groups of patients with high and low fibrinogen levels, while the predictors of exacerbation were analyzed using Cox proportional hazards regression. Results: Patients with non-CF bronchiectasis carried higher fibrinogen (3.00 ± 2.31 vs. 1.52 ± 0.74 µg/mL; p = 0.016) and adiponectin (12.3 ± 5.07 vs. 9.17 ± 5.30 µg/mL; p = 0.031) levels compared with healthy controls. The serum level of angiopoietin-2 was comparable between the two groups (1.49 ± 0.96 vs. 1.21 ± 0.79 ng/mL, p = 0.277). Correlations of adiponectin and angiopoietin-2 with BSI and FACED scores were not significant. However, there were significant correlations between fibrinogen and both BSI (r = 0.428) and FACED scores (r = 0.484). Multivariate linear regression analysis revealed that fibrinogen level was an independent variable associated with both BSI and FACED scores. A total of 31 (50.8%) out of 61 patients experienced exacerbation during the follow-up period of 25.4 months. Exacerbation-free survival was significantly longer in patients with low fibrinogen levels than in those with high fibrinogen (log-rank test, p = 0.034). High fibrinogen levels and Pseudomonas colonization were independent risk factors for future exacerbation (HR 2.308; p = 0.03 and HR 2.555; p = 0.02, respectively). Conclusions: Serum fibrinogen, but not adiponectin or angiopoietin-2, is a potential biomarker closely associated with the severity and exacerbation of non-CF bronchiectasis.
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Stevens RP, Alexeyev MF, Kozhukhar N, Pastukh V, Paudel SS, Bell J, Tambe DT, Stevens T, Lee JY. Carbonic anhydrase IX proteoglycan-like and intracellular domains mediate pulmonary microvascular endothelial cell repair and angiogenesis. Am J Physiol Lung Cell Mol Physiol 2022; 323:L48-L57. [PMID: 35672011 DOI: 10.1152/ajplung.00337.2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The lungs of patients with acute respiratory distress syndrome (ARDS) have hyperpermeable capillaries that must undergo repair in an acidic microenvironment. Pulmonary microvascular endothelial cells (PMVECs) have an acid-resistant phenotype, in part due to carbonic anhydrase IX (CA IX). CA IX also facilitates PMVEC repair by promoting aerobic glycolysis, migration, and network formation. Molecular mechanisms of how CA IX performs such a wide range of functions are unknown. CA IX is comprised of four domains known as the proteoglycan-like (PG), catalytic (CA), transmembrane (TM), and intracellular (IC) domains. We hypothesized that the PG and CA domains mediate PMVEC pH homeostasis and repair, and the IC domain regulates aerobic glycolysis and PI3k/Akt signaling. The functions of each CA IX domain were investigated using PMVEC cell lines that express either a full-length CA IX protein or a CA IX protein harboring a domain deletion. We found that the PG domain promotes intracellular pH homeostasis, migration, and network formation. The CA and IC domains mediate Akt activation but negatively regulate aerobic glycolysis. The IC domain also supports migration while inhibiting network formation. Finally, we show that exposure to acidosis suppresses aerobic glycolysis and migration, even though intracellular pH is maintained in PMVECs. Thus, we report that 1) The PG and IC domains mediate PMVEC migration and network formation, 2) the CA and IC domains support PI3K/Akt signaling, and 3) acidosis impairs PMVEC metabolism and migration independent of intracellular pH homeostasis.
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Affiliation(s)
- Reece P Stevens
- Department of Physiology and Cell Biology, University of South Alabama, Mobile, AL, United States.,Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, AL, United States
| | - Mikhail F Alexeyev
- Department of Physiology and Cell Biology, University of South Alabama, Mobile, AL, United States.,Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, AL, United States
| | - Natalya Kozhukhar
- Department of Physiology and Cell Biology, University of South Alabama, Mobile, AL, United States.,Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, AL, United States
| | - Viktoriya Pastukh
- Department of Physiology and Cell Biology, University of South Alabama, Mobile, AL, United States.,Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, AL, United States
| | - Sunita S Paudel
- Department of Physiology and Cell Biology, University of South Alabama, Mobile, AL, United States.,Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, AL, United States
| | - Jessica Bell
- Department of Physiology and Cell Biology, University of South Alabama, Mobile, AL, United States.,Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, AL, United States
| | - Dhananjay T Tambe
- Department of Mechanical, Aerospace, and Biomedical Engineering, College of Medicine, University of South Alabama, Mobile, Alabama, United States.,Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, AL, United States
| | - Troy Stevens
- Department of Physiology and Cell Biology, University of South Alabama, Mobile, AL, United States.,Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, AL, United States
| | - Ji Young Lee
- Department of Physiology and Cell Biology, University of South Alabama, Mobile, AL, United States.,Department of Internal Medicine, College of Medicine, University of South Alabama, Mobile, Alabama, United States.,Division of Pulmonary and Critical Care Medicine, College of Medicine, University of South Alabama, Mobile, AL, United States.,Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, AL, United States
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7
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Cheng Y, Gu W, Zhang G, Guo X. Notch1 activation of Jagged1 contributes to differentiation of mesenchymal stem cells into endothelial cells under cigarette smoke extract exposure. BMC Pulm Med 2022; 22:139. [PMID: 35410206 PMCID: PMC9004089 DOI: 10.1186/s12890-022-01913-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 03/23/2022] [Indexed: 11/30/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) have shown therapeutic potential for engraftment to, differentiation into, endothelial cells (ECs). However, low-efficiency yields hinder their use as ECs for therapeutic vascularization. Methods The Notch1 signaling pathway is key to optimal pulmonary development. Recent evidence has shown that this pathway participated in angiogenesis. Herein, we found that in MSCs, Jagged1 was a target for Notch 1, resulting in a positive feedback loop that propagated a wave of ECs differentiation. Results In vitro, Jagged1 was found to be activated by Notch1 in MSCs, resulting in the RBP-Jκ-dependent expression of Jagged1 mRNA, a response that was blocked by Notch1 inhibition. Notch1 promoted the formation of cord-like structures on Matrigel. However, cigarette smoke extract inhibited this process, compared to that in control groups. Moreover, Notch1-overexpressing cells upregulated the expressing of HIF-1α gene. The HIF-1α was an angiogenic factor that clustered with Notch1, underscoring the critical role of Notch1 pathway in vessel assembly. Interestingly, this was abrogated by incubation with Notch1 shRNA. Conclusions Notch signaling pathway promotes differentiation of MSCs in to ECs. It also regulates angiogenesis and transcription of specific markers on ECs. These results provide a mechanism that regulates differentiation of MSCs into ECs phenotypes. Supplementary Information The online version contains supplementary material available at 10.1186/s12890-022-01913-3.
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Affiliation(s)
- Yi Cheng
- Department of Respiratory Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China
| | - Wen Gu
- Department of Respiratory Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China
| | - Guorui Zhang
- Department of Respiratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xuejun Guo
- Department of Respiratory Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China.
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Valdoz JC, Franks NA, Cribbs CG, Jacobs DJ, Dodson EL, Knight CJ, Poulson PD, Garfield SR, Johnson BC, Hemeyer BM, Sudo MT, Saunooke JA, Kartchner BC, Saxton A, Vallecillo-Zuniga ML, Santos M, Chamberlain B, Christensen KA, Nordin GP, Narayanan AS, Raghu G, Van Ry PM. Soluble ECM promotes organotypic formation in lung alveolar model. Biomaterials 2022; 283:121464. [DOI: 10.1016/j.biomaterials.2022.121464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 02/15/2022] [Accepted: 03/06/2022] [Indexed: 11/25/2022]
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9
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Sriram K, Insel MB, Insel PA. Inhaled β2 Adrenergic Agonists and Other cAMP-Elevating Agents: Therapeutics for Alveolar Injury and Acute Respiratory Disease Syndrome? Pharmacol Rev 2021; 73:488-526. [PMID: 34795026 DOI: 10.1124/pharmrev.121.000356] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 08/15/2021] [Indexed: 12/15/2022] Open
Abstract
Inhaled long-acting β-adrenergic agonists (LABAs) and short-acting β-adrenergic agonists are approved for the treatment of obstructive lung disease via actions mediated by β2 adrenergic receptors (β2-ARs) that increase cellular cAMP synthesis. This review discusses the potential of β2-AR agonists, in particular LABAs, for the treatment of acute respiratory distress syndrome (ARDS). We emphasize ARDS induced by pneumonia and focus on the pathobiology of ARDS and actions of LABAs and cAMP on pulmonary and immune cell types. β2-AR agonists/cAMP have beneficial actions that include protection of epithelial and endothelial cells from injury, restoration of alveolar fluid clearance, and reduction of fibrotic remodeling. β2-AR agonists/cAMP also exert anti-inflammatory effects on the immune system by actions on several types of immune cells. Early administration is likely critical for optimizing efficacy of LABAs or other cAMP-elevating agents, such as agonists of other Gs-coupled G protein-coupled receptors or cyclic nucleotide phosphodiesterase inhibitors. Clinical studies that target lung injury early, prior to development of ARDS, are thus needed to further assess the use of inhaled LABAs, perhaps combined with inhaled corticosteroids and/or long-acting muscarinic cholinergic antagonists. Such agents may provide a multipronged, repurposing, and efficacious therapeutic approach while minimizing systemic toxicity. SIGNIFICANCE STATEMENT: Acute respiratory distress syndrome (ARDS) after pulmonary alveolar injury (e.g., certain viral infections) is associated with ∼40% mortality and in need of new therapeutic approaches. This review summarizes the pathobiology of ARDS, focusing on contributions of pulmonary and immune cell types and potentially beneficial actions of β2 adrenergic receptors and cAMP. Early administration of inhaled β2 adrenergic agonists and perhaps other cAMP-elevating agents after alveolar injury may be a prophylactic approach to prevent development of ARDS.
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Affiliation(s)
- Krishna Sriram
- Departments of Pharmacology (K.S., P.A.I.) and Medicine (P.A.I.), University of California San Diego, La Jolla, California; Department of Medicine (M.B.I.) University of Arizona, Tucson, Arizona
| | - Michael B Insel
- Departments of Pharmacology (K.S., P.A.I.) and Medicine (P.A.I.), University of California San Diego, La Jolla, California; Department of Medicine (M.B.I.) University of Arizona, Tucson, Arizona
| | - Paul A Insel
- Departments of Pharmacology (K.S., P.A.I.) and Medicine (P.A.I.), University of California San Diego, La Jolla, California; Department of Medicine (M.B.I.) University of Arizona, Tucson, Arizona
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10
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Suresh NT, Ravindran VE, Krishnakumar U. A Computational Framework to Identify Cross Association Between Complex Disorders by Protein-protein Interaction Network Analysis. Curr Bioinform 2021. [DOI: 10.2174/1574893615999200724145434] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Objective:
It is a known fact that numerous complex disorders do not happen in
isolation indicating the plausible set of shared causes common to several different sicknesses.
Hence, analysis of comorbidity can be utilized to explore the association between several
disorders. In this study, we have proposed a network-based computational approach, in which
genes are organized based on the topological characteristics of the constructed Protein-Protein
Interaction Network (PPIN) followed by a network prioritization scheme, to identify distinctive
key genes and biological pathways shared among diseases.
Methods:
The proposed approach is initiated from constructed PPIN of any randomly chosen
disease genes in order to infer its associations with other diseases in terms of shared pathways, coexpression,
co-occurrence etc. For this, initially, proteins associated to any disease based on
random choice were identified. Secondly, PPIN is organized through topological analysis to define
hub genes. Finally, using a prioritization algorithm a ranked list of newly predicted
multimorbidity-associated proteins is generated. Using Gene Ontology (GO), cellular pathways
involved in multimorbidity-associated proteins are mined.
Result and Conclusion:
: The proposed methodology is tested using three disorders, namely
Diabetes, Obesity and blood pressure at an atomic level and the results suggest the comorbidity of
other complex diseases that have associations with the proteins included in the disease of present
study through shared proteins and pathways. For diabetes, we have obtained key genes like
GAPDH, TNF, IL6, AKT1, ALB, TP53, IL10, MAPK3, TLR4 and EGF with key pathways like
P53 pathway, VEGF signaling pathway, Ras Pathway, Interleukin signaling pathway, Endothelin
signaling pathway, Huntington disease etc. Studies on other disorders such as obesity and blood
pressure also revealed promising results.
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Affiliation(s)
- Nikhila T. Suresh
- Department of Computer Science and IT, Amrita School of Arts and Sciences, Amrita Vishwa Vidyapeetham, Kochi Campus, Kochi, India
| | - Vimina E. Ravindran
- Department of Computer Science and IT, Amrita School of Arts and Sciences, Amrita Vishwa Vidyapeetham, Kochi Campus, Kochi, India
| | - Ullattil Krishnakumar
- Department of Computer Science and IT, Amrita School of Arts and Sciences, Amrita Vishwa Vidyapeetham, Kochi Campus, Kochi, India
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11
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Liu G, Philp AM, Corte T, Travis MA, Schilter H, Hansbro NG, Burns CJ, Eapen MS, Sohal SS, Burgess JK, Hansbro PM. Therapeutic targets in lung tissue remodelling and fibrosis. Pharmacol Ther 2021; 225:107839. [PMID: 33774068 DOI: 10.1016/j.pharmthera.2021.107839] [Citation(s) in RCA: 150] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 03/03/2021] [Indexed: 02/07/2023]
Abstract
Structural changes involving tissue remodelling and fibrosis are major features of many pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Abnormal deposition of extracellular matrix (ECM) proteins is a key factor in the development of tissue remodelling that results in symptoms and impaired lung function in these diseases. Tissue remodelling in the lungs is complex and differs between compartments. Some pathways are common but tissue remodelling around the airways and in the parenchyma have different morphologies. Hence it is critical to evaluate both common fibrotic pathways and those that are specific to different compartments; thereby expanding the understanding of the pathogenesis of fibrosis and remodelling in the airways and parenchyma in asthma, COPD and IPF with a view to developing therapeutic strategies for each. Here we review the current understanding of remodelling features and underlying mechanisms in these major respiratory diseases. The differences and similarities of remodelling are used to highlight potential common therapeutic targets and strategies. One central pathway in remodelling processes involves transforming growth factor (TGF)-β induced fibroblast activation and myofibroblast differentiation that increases ECM production. The current treatments and clinical trials targeting remodelling are described, as well as potential future directions. These endeavours are indicative of the renewed effort and optimism for drug discovery targeting tissue remodelling and fibrosis.
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Affiliation(s)
- Gang Liu
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Sydney, NSW, Australia
| | - Ashleigh M Philp
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Sydney, NSW, Australia; St Vincent's Medical School, UNSW Medicine, UNSW, Sydney, NSW, Australia
| | - Tamera Corte
- Royal Prince Alfred Hospital, Camperdown, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Mark A Travis
- The Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Sciences Centre and Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, United Kingdom
| | - Heidi Schilter
- Pharmaxis Ltd, 20 Rodborough Road, Frenchs Forest, Sydney, NSW, Australia
| | - Nicole G Hansbro
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Sydney, NSW, Australia
| | - Chris J Burns
- Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Mathew S Eapen
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, University of Tasmania, Launceston, TAS, Australia
| | - Sukhwinder S Sohal
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, University of Tasmania, Launceston, TAS, Australia
| | - Janette K Burgess
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Department of Pathology and Medical Biology, Groningen, The Netherlands; Woolcock Institute of Medical Research, Discipline of Pharmacology, The University of Sydney, Sydney, NSW, Australia
| | - Philip M Hansbro
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Sydney, NSW, Australia.
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12
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Twist1 signaling in age-dependent decline in angiogenesis and lung regeneration. Aging (Albany NY) 2021; 13:7781-7799. [PMID: 33764901 PMCID: PMC8034921 DOI: 10.18632/aging.202875] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 03/14/2021] [Indexed: 12/11/2022]
Abstract
Angiogenesis – the formation of new blood capillaries- is impaired in aging animals and contributes to the pathogenesis of age-related diseases. A transcription factor, Twist1, contributes to the pathogenesis of age- and angiogenesis-related diseases such as pulmonary fibrosis and atherosclerosis. However, the mechanism by which Twist1 controls age-dependent decline in angiogenesis remains unclear. In this report, we have demonstrated that the levels of Twist1 are higher, while the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) that stimulates angiogenesis, is lower in endothelial cells (ECs) isolated from aged human adipose tissues and mouse lungs compared to those from young tissues. Knockdown of Twist1 in aged human ECs increases the levels of PGC1α and angiogenic factor receptor, vascular endothelial growth factor receptor (VEGFR2), and restores EC proliferation and migration, while inhibition of PGC1α suppresses these effects. Knockdown of Twist1 in supplemented aged ECs also restores vascular networks in the subcutaneously implanted gel, while these effects are abrogated by knockdown of PGC1α. Age-dependent inhibition of post-pneumonectomy (PNX) lung growth is suppressed in Tie2-specific Twist1 conditional knockout mouse lungs, in which VEGFR2 expression increases after PNX. These results suggest that upregulation of endothelial Twist1 mediates age-dependent decline in angiogenesis and regenerative lung growth.
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13
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Roy HS, Singh R, Ghosh D. SARS-CoV-2 and tissue damage: current insights and biomaterial-based therapeutic strategies. Biomater Sci 2021; 9:2804-2824. [PMID: 33666206 DOI: 10.1039/d0bm02077j] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The effect of SARS-CoV-2 infection on humanity has gained worldwide attention and importance due to the rapid transmission, lack of treatment options and high mortality rate of the virus. While scientists across the world are searching for vaccines/drugs that can control the spread of the virus and/or reduce the risks associated with infection, patients infected with SARS-CoV-2 have been reported to have tissue/organ damage. With most tissues/organs having limited regenerative potential, interventions that prevent further damage or facilitate healing would be helpful. In the past few decades, biomaterials have gained prominence in the field of tissue engineering, in view of their major role in the regenerative process. Here we describe the effect of SARS-CoV-2 on multiple tissues/organs, and provide evidence for the positive role of biomaterials in aiding tissue repair. These findings are further extrapolated to explore their prospects as a therapeutic platform to address the tissue/organ damage that is frequently observed during this viral outbreak. This study suggests that the biomaterial-based approach could be an effective strategy for regenerating tissues/organs damaged by SARS-CoV-2.
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Affiliation(s)
- Himadri Shekhar Roy
- Department of Biological Science, Institute of Nanoscience and Technology (INST), Habitat Centre, Sector 64, Phase 10, Mohali-160062, Punjab, India.
| | - Rupali Singh
- Department of Biological Science, Institute of Nanoscience and Technology (INST), Habitat Centre, Sector 64, Phase 10, Mohali-160062, Punjab, India.
| | - Deepa Ghosh
- Department of Biological Science, Institute of Nanoscience and Technology (INST), Habitat Centre, Sector 64, Phase 10, Mohali-160062, Punjab, India.
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14
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Respiratory viral infections during pregnancy: effects of SARS-CoV-2 and other related viruses over the offspring. J Dev Orig Health Dis 2021; 13:3-8. [PMID: 33526164 DOI: 10.1017/s2040174420001373] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Little is known about the consequences of viral infection for pregnant woman or for the fetus. This issue became important with the appearance of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The infection with SARS-CoV-2 causes a respiratory syndrome known as COVID-19. The fast spreading around the world and the fact that without a treatment or vaccine humans are completely exposed, converts emerging viral diseases in a significant risk for pregnant women and their infants. At this time, during SARS-CoV-2 pandemics pregnant women are not considered as a risk population and little is known about the effects of viral infections over the offspring although the amount of emerging evidence showing detrimental effects for the mother and the fetus. This issue highlights the importance to understand the effects of viral infections during pregnancy. In this work, we analyze the effects of viral infections, like SARS-CoV-2 and other related viruses during pregnancy over the mother and the consequences for the offspring.
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15
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Summers ME, Richmond BW, Kropski JA, Majka SA, Bastarache JA, Hatzopoulos AK, Bylund J, Ghosh M, Petrache I, Foronjy RF, Geraghty P, Majka SM. Balanced Wnt/Dickkopf-1 signaling by mesenchymal vascular progenitor cells in the microvascular niche maintains distal lung structure and function. Am J Physiol Cell Physiol 2021; 320:C119-C131. [PMID: 33085496 PMCID: PMC7846975 DOI: 10.1152/ajpcell.00277.2020] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 09/29/2020] [Accepted: 10/12/2020] [Indexed: 02/08/2023]
Abstract
The well-described Wnt inhibitor Dickkopf-1 (DKK1) plays a role in angiogenesis as well as in regulation of growth factor signaling cascades in pulmonary remodeling associated with chronic lung diseases (CLDs) including emphysema and fibrosis. However, the specific mechanisms by which DKK1 influences mesenchymal vascular progenitor cells (MVPCs), microvascular endothelial cells (MVECs), and smooth muscle cells (SMCs) within the microvascular niche have not been elucidated. In this study, we show that knockdown of DKK1 in Abcg2pos lung mouse adult tissue resident MVPCs alters lung stiffness, parenchymal collagen deposition, microvessel muscularization and density as well as loss of tissue structure in response to hypoxia exposure. To complement the in vivo mouse modeling, we also identified cell- or disease-specific responses to DKK1, in primary lung chronic obstructive pulmonary disease (COPD) MVPCs, COPD MVECs, and SMCs, supporting a paradoxical disease-specific response of cells to well-characterized factors. Cell responses to DKK1 were dose dependent and correlated with varying expressions of the DKK1 receptor, CKAP4. These data demonstrate that DKK1 expression is necessary to maintain the microvascular niche whereas its effects are context specific. They also highlight DKK1 as a regulatory candidate to understand the role of Wnt and DKK1 signaling between cells of the microvascular niche during tissue homeostasis and during the development of chronic lung diseases.
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Affiliation(s)
- Megan E Summers
- Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado
| | - Bradley W Richmond
- Division of Allergy, Pulmonary and Critical Care Medicine or Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Veterans Affairs Medical Center, Nashville, Tennessee
| | - Jonathan A Kropski
- Division of Allergy, Pulmonary and Critical Care Medicine or Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Veterans Affairs Medical Center, Nashville, Tennessee
| | - Sarah A Majka
- Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado
| | - Julie A Bastarache
- Division of Allergy, Pulmonary and Critical Care Medicine or Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Veterans Affairs Medical Center, Nashville, Tennessee
| | - Antonis K Hatzopoulos
- Division of Allergy, Pulmonary and Critical Care Medicine or Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Veterans Affairs Medical Center, Nashville, Tennessee
| | - Jeffery Bylund
- Division of Allergy, Pulmonary and Critical Care Medicine or Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Veterans Affairs Medical Center, Nashville, Tennessee
| | - Moumita Ghosh
- Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado
| | - Irina Petrache
- Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado
| | - Robert F Foronjy
- Division of Pulmonary and Critical Care Medicine, SUNY Downstate Medical Center, Brooklyn, New York
| | - Patrick Geraghty
- Division of Pulmonary and Critical Care Medicine, SUNY Downstate Medical Center, Brooklyn, New York
| | - Susan M Majka
- Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado
- Department of Medicine, Pulmonary & Critical Care Medicine, Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado, Aurora, Colorado
- Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado, Aurora, Colorado
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16
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Seyfoori A, Amereh M, Dabiri SMH, Askari E, Walsh T, Akbari M. The role of biomaterials and three dimensional (3D) in vitro tissue models in fighting against COVID-19. Biomater Sci 2020; 9:1217-1226. [PMID: 33355542 DOI: 10.1039/d0bm01616k] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Over the past century, viral respiratory pandemics have been a leading cause of infectious disease worldwide. A deep understanding of the underlying mechanisms of the viral interactions with host cells at the target sites is necessary for a rapid response to such pandemics. To meet this aim, various testing platforms are required to recapitulate the pathophysiological behavior of the virus within the respiratory tract. These bioengineered platforms can effectively be used for the development of different therapeutics and vaccines. This paper briefly reviews the progress in the areas of biomaterial use for pulmonary tissue regeneration and integration with current bioengineered platforms including engineered tissues, organoids, and organs-on-a-chip platforms for viral respiratory disease studies. Finally, a brief overview of the opportunities presented by organ-on-a-chip systems for studying COVID-19 and subsequent drug development is introduced.
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Affiliation(s)
- Amir Seyfoori
- Laboratory for Innovations in Micro Engineering (LiME), Department of Mechanical Engineering, University of Victoria, Victoria, Canada.
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17
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Strassheim D, Verin A, Batori R, Nijmeh H, Burns N, Kovacs-Kasa A, Umapathy NS, Kotamarthi J, Gokhale YS, Karoor V, Stenmark KR, Gerasimovskaya E. P2Y Purinergic Receptors, Endothelial Dysfunction, and Cardiovascular Diseases. Int J Mol Sci 2020; 21:ijms21186855. [PMID: 32962005 PMCID: PMC7555413 DOI: 10.3390/ijms21186855] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 09/11/2020] [Accepted: 09/15/2020] [Indexed: 12/13/2022] Open
Abstract
Purinergic G-protein-coupled receptors are ancient and the most abundant group of G-protein-coupled receptors (GPCRs). The wide distribution of purinergic receptors in the cardiovascular system, together with the expression of multiple receptor subtypes in endothelial cells (ECs) and other vascular cells demonstrates the physiological importance of the purinergic signaling system in the regulation of the cardiovascular system. This review discusses the contribution of purinergic P2Y receptors to endothelial dysfunction (ED) in numerous cardiovascular diseases (CVDs). Endothelial dysfunction can be defined as a shift from a “calm” or non-activated state, characterized by low permeability, anti-thrombotic, and anti-inflammatory properties, to a “activated” state, characterized by vasoconstriction and increased permeability, pro-thrombotic, and pro-inflammatory properties. This state of ED is observed in many diseases, including atherosclerosis, diabetes, hypertension, metabolic syndrome, sepsis, and pulmonary hypertension. Herein, we review the recent advances in P2Y receptor physiology and emphasize some of their unique signaling features in pulmonary endothelial cells.
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Affiliation(s)
- Derek Strassheim
- The Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Aurora, CO 80045, USA; (D.S.); (N.B.); (V.K.); (K.R.S.)
| | - Alexander Verin
- Vascular Biology Center, Augusta University, Augusta, GA 30912, USA; (A.V.); (R.B.); (A.K.-K.)
| | - Robert Batori
- Vascular Biology Center, Augusta University, Augusta, GA 30912, USA; (A.V.); (R.B.); (A.K.-K.)
| | - Hala Nijmeh
- The Department of Pediatrics, Division of Critical Care Medicine, University of Colorado Denver, Aurora, CO 80045, USA;
| | - Nana Burns
- The Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Aurora, CO 80045, USA; (D.S.); (N.B.); (V.K.); (K.R.S.)
| | - Anita Kovacs-Kasa
- Vascular Biology Center, Augusta University, Augusta, GA 30912, USA; (A.V.); (R.B.); (A.K.-K.)
| | | | - Janavi Kotamarthi
- The Department of BioMedical Engineering, University of Wisconsin, Madison, WI 53706, USA; (J.K.); (Y.S.G.)
| | - Yash S. Gokhale
- The Department of BioMedical Engineering, University of Wisconsin, Madison, WI 53706, USA; (J.K.); (Y.S.G.)
| | - Vijaya Karoor
- The Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Aurora, CO 80045, USA; (D.S.); (N.B.); (V.K.); (K.R.S.)
| | - Kurt R. Stenmark
- The Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Aurora, CO 80045, USA; (D.S.); (N.B.); (V.K.); (K.R.S.)
- The Department of Pediatrics, Division of Critical Care Medicine, University of Colorado Denver, Aurora, CO 80045, USA;
| | - Evgenia Gerasimovskaya
- The Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Aurora, CO 80045, USA; (D.S.); (N.B.); (V.K.); (K.R.S.)
- The Department of Pediatrics, Division of Critical Care Medicine, University of Colorado Denver, Aurora, CO 80045, USA;
- Correspondence: ; Tel.: +1-303-724-5614
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18
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Cao D, Mikosz AM, Ringsby AJ, Anderson KC, Beatman EL, Koike K, Petrache I. MicroRNA-126-3p Inhibits Angiogenic Function of Human Lung Microvascular Endothelial Cells via LAT1 (L-Type Amino Acid Transporter 1)-Mediated mTOR (Mammalian Target of Rapamycin) Signaling. Arterioscler Thromb Vasc Biol 2020; 40:1195-1206. [PMID: 32212853 PMCID: PMC7370836 DOI: 10.1161/atvbaha.119.313800] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 03/13/2020] [Indexed: 12/13/2022]
Abstract
OBJECTIVE MicroRNA-126-3p (miR-126) is required for angiogenesis during organismal development or the repair of injured arterial vasculature. The role of miR-126 in lung microvascular endothelial cells, which are essential for gas exchange and for lung injury repair and regeneration, remains poorly understood. Considering the significant heterogeneity of endothelial cells from different vascular beds, we aimed to determine the role of miR-126 in regulating lung microvascular endothelial cell function and to elucidate its downstream signaling pathways. Approach and Results: Overexpression and knockdown of miR-126 in primary human lung microvascular endothelial cells (HLMVEC) were achieved via transfections of miR-126 mimics and antisense inhibitors. Increasing miR-126 levels in HLMVEC reduced cell proliferation, weakened tube formation, and increased cell apoptosis, whereas decreased miR-126 levels stimulated cell proliferation and tube formation. Whole-genome RNA sequencing revealed that miR-126 was associated with an antiangiogenic and proapoptotic transcriptomic profile. Using validation assays and knockdown approaches, we identified that the effect of miR-126 on HLMVEC angiogenesis was mediated by the LAT1 (L-type amino acid transporter 1), via regulation of mTOR (mammalian target of rapamycin) signaling. Furthermore, downregulation of miR-126 in HLMVEC inhibited cell apoptosis and improved endothelial tube formation during exposure to environmental insults such as cigarette smoke. CONCLUSIONS miR-126 inhibits HLMVEC angiogenic function by targeting the LAT1-mTOR signaling axis, suggesting that miR-126 inhibition may be useful for conditions associated with microvascular loss, whereas miR-126 augmentation may help control unwanted microvascular angiogenesis.
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Affiliation(s)
- Danting Cao
- Department of Pharmacology Graduate Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO
- Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO
| | - Andrew M. Mikosz
- Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO
| | - Alexandra J. Ringsby
- Department of Chemical and Biomolecular Engineering, University of California Berkeley, Berkeley, CA
| | - Kelsey C. Anderson
- Center for Genes, Environment and Health, National Jewish Health, Denver, CO
| | - Erica L. Beatman
- Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO
| | - Kengo Koike
- Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO
- Division of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, Japan
| | - Irina Petrache
- Department of Pharmacology Graduate Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO
- Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO
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19
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Majka SM, Rojas M, Petrache I, Foronjy RF. Mesenchymal Regulation of the Microvascular Niche in Chronic Lung Diseases. Compr Physiol 2019; 9:1431-1441. [PMID: 31688970 DOI: 10.1002/cphy.c180043] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
The adult lung is comprised of diverse vascular, epithelial, and mesenchymal progenitor cell populations that reside in distinct niches. Mesenchymal progenitor cells (MPCs) are intimately associated with both the epithelium and the vasculature, and new evidence is emerging to describe their functional roles in these niches. Also emerging, following lineage analysis and single cell sequencing, is a new understanding of the diversity of mesenchymal cell subpopulations in the lung. However, several gaps in knowledge remain, including how newly defined MPC lineages interact with cells in the vascular niche and the role of adult lung MPCs during lung repair and regeneration following injury, especially in chronic lung diseases. Here we summarize how the current evidence on MPC regulation of the microvasculature during tissue homeostasis and injury may inform studies on understanding their role in chronic lung disease pathogenesis or repair. © 2019 American Physiological Society. Compr Physiol 9:1431-1441, 2019.
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Affiliation(s)
- Susan M Majka
- Department of Medicine, Division of Pulmonary, Critical Care & Sleep Medicine, National Jewish Health, Denver, Colorado, USA
| | - Mauricio Rojas
- McGowan Institute for Regenerative Medicine, Simmons Center for Interstitial Lung Disease, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Irina Petrache
- Department of Medicine, Division of Pulmonary, Critical Care & Sleep Medicine, National Jewish Health, Denver, Colorado, USA
| | - Robert F Foronjy
- Division of Pulmonary and Critical Care Medicine, SUNY Downstate Medical Center, Brooklyn, New York, USA
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20
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Optimization of Pulmonary Vasculature Tridimensional Phenotyping in The Rat Fetus. Sci Rep 2019; 9:1244. [PMID: 30718645 PMCID: PMC6362188 DOI: 10.1038/s41598-018-37906-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Accepted: 12/11/2018] [Indexed: 01/10/2023] Open
Abstract
Comparative, functional, developmental, and some morphological studies on animal anatomy require accurate visualization of three-dimensional structures. Nowadays, several widely applicable methods exist for non-destructive whole-mount imaging of animal tissues. The purpose of this study was to optimize specimen preparation and develop a method for quantitative analysis of the total pulmonary vasculature in fetal rats. Tissues were harvested at E21 and fetuses fixed overnight in 4% paraformaldehyde/phosphate buffered saline. They were treated with 25% Lugol solution for 72 hours to ensure perfusion. Four different methods were used for fetal specimen preparation; isolated lung, upper torso, direct right ventricle contrast injection, and whole body with partial thoracic skin excision. The microCT scan was performed, and pulmonary vasculature was segmented. Vessels were analyzed for diameter, length, and branching. Of the four preparation methods, only whole body with partial thoracic skin excision resulted in adequate reconstruction of the pulmonary vasculature. In silico generated 3D images gathered by micro CT showed pulmonary vasculature distributed throughout the lung, which was representative of the shape and structure of the lungs. The mean number of vessels segmented in the pulmonary tree was 900 ± 24 with a mean diameter of 134.13 µm (range 40.72–265.69 µm). While up to the 30th generation of vessels could be segmented, both for arteries and veins, the majority of branching was between the 21st and 30th generations. Passive diffusion of contrast material enables quantitative analysis of the fetal pulmonary vasculature. This technique is a useful tool to analyze the characteristics and quantify the fetal pulmonary vasculature.
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21
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Fakoya AOJ, Otohinoyi DA, Yusuf J. Current Trends in Biomaterial Utilization for Cardiopulmonary System Regeneration. Stem Cells Int 2018; 2018:3123961. [PMID: 29853910 PMCID: PMC5949153 DOI: 10.1155/2018/3123961] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 11/15/2017] [Accepted: 03/01/2018] [Indexed: 12/28/2022] Open
Abstract
The cardiopulmonary system is made up of the heart and the lungs, with the core function of one complementing the other. The unimpeded and optimal cycling of blood between these two systems is pivotal to the overall function of the entire human body. Although the function of the cardiopulmonary system appears uncomplicated, the tissues that make up this system are undoubtedly complex. Hence, damage to this system is undesirable as its capacity to self-regenerate is quite limited. The surge in the incidence and prevalence of cardiopulmonary diseases has reached a critical state for a top-notch response as it currently tops the mortality table. Several therapies currently being utilized can only sustain chronically ailing patients for a short period while they are awaiting a possible transplant, which is also not devoid of complications. Regenerative therapeutic techniques now appear to be a potential approach to solve this conundrum posed by these poorly self-regenerating tissues. Stem cell therapy alone appears not to be sufficient to provide the desired tissue regeneration and hence the drive for biomaterials that can support its transplantation and translation, providing not only physical support to seeded cells but also chemical and physiological cues to the cells to facilitate tissue regeneration. The cardiac and pulmonary systems, although literarily seen as just being functionally and spatially cooperative, as shown by their diverse and dissimilar adult cellular and tissue composition has been proven to share some common embryological codevelopment. However, necessitating their consideration for separate review is the immense adult architectural difference in these systems. This review also looks at details on new biological and synthetic biomaterials, tissue engineering, nanotechnology, and organ decellularization for cardiopulmonary regenerative therapies.
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Affiliation(s)
| | | | - Joshua Yusuf
- All Saints University School of Medicine, Roseau, Dominica
- All Saints University School of Medicine, Kingstown, Saint Vincent and the Grenadines
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22
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Meng L, Wang C, Wang Z, Yin T, Liu Z, Qin H, Zhang Y, Gu X, Yu X, Jiang L, Zhang X. Feixian Recipe inhibits pulmonary fibrosis by targeting pulmonary microvascular endothelial cells and VEGF/VEGFR2 signaling pathway. TRADITIONAL MEDICINE AND MODERN MEDICINE 2018. [DOI: 10.1142/s2575900018500052] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Objective: To investigate the regulatory mechanism of PMVECs and vascular endothelial growth factor VEGF/vascular endothelial growth factor receptor 2 (VEGFR2) signaling pathway in pulmonary fibrosis and the inhibitory effect of Feixian Recipe (FXR) in pulmonary fibrosis by targeting VEGF/VEGFR2 signal pathway. Methods: In this study, pulmonary microvascular endothelial cells (PMVECs) were successfully isolated from rats with pulmonary fibrosis. Cells were divided into six groups: model group, prednisone group, losartan group and three different concentrated (100[Formula: see text]ug/mL, 60[Formula: see text]ug/mL, 20[Formula: see text]ug/mL) FXR groups. The adhesion rate, migration and closed blood vessels of each PMVECs group were detected. The mRNA expression of VEGF, VEGFR2, phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinases 38 (P38 MAPK) and activin receptor-like kinase (ALK) were detected by SYBR Green I real-time fluorescence quantitative PCR. Results: Compared with the model group, the adhesion rate, migration and angiogenesis of PMVECs were decreased in FXR groups ([Formula: see text]). Compared with prednisone and losartan groups, the mRNA expressions of VEGF, VEGFR2, PI3K and P38 MAPK were down-regulated significantly by FXR ([Formula: see text]). Conclution: FXR can inhibit the migration, adhesion and angiogenesis of PMVECs in rats with pulmonary fibrosis by targeting VEGF/VEGFR2 signal pathway, and inhibit the progress of pulmonary fibrosis.
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Affiliation(s)
- Lihong Meng
- Second Clinical Medical School, Beijing University of Chinese Medicine, Beijing 100029, P. R. China
- Department of Respiratory Medicine, Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100078, P. R. China
| | - Chen Wang
- Second Clinical Medical School, Beijing University of Chinese Medicine, Beijing 100029, P. R. China
| | - Zijuan Wang
- Second Clinical Medical School, Beijing University of Chinese Medicine, Beijing 100029, P. R. China
- Department of Respiratory Medicine, Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100078, P. R. China
| | - Ting Yin
- Department of Respiratory Medicine, Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100078, P. R. China
| | - Zhe Liu
- Second Clinical Medical School, Beijing University of Chinese Medicine, Beijing 100029, P. R. China
- Department of Respiratory Medicine, Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100078, P. R. China
| | - Huihui Qin
- Second Clinical Medical School, Beijing University of Chinese Medicine, Beijing 100029, P. R. China
| | - Yuting Zhang
- Second Clinical Medical School, Beijing University of Chinese Medicine, Beijing 100029, P. R. China
- Department of Respiratory Medicine, Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100078, P. R. China
| | - Xiaofeng Gu
- Second Clinical Medical School, Beijing University of Chinese Medicine, Beijing 100029, P. R. China
- Department of Respiratory Medicine, Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100078, P. R. China
| | - Xiaolin Yu
- Second Clinical Medical School, Beijing University of Chinese Medicine, Beijing 100029, P. R. China
- Department of Respiratory Medicine, Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100078, P. R. China
| | - Liangduo Jiang
- Department of Respiratory Medicine, Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100078, P. R. China
| | - Xiaomei Zhang
- Department of Respiratory Medicine, Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100078, P. R. China
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23
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Abstract
Pulmonary hypertension that develops in the setting of underlying lung diseases such as COPD or idiopathic pulmonary fibrosis (IPF) is associated with decreased functional status, worsening hypoxemia and quality of life, and increased mortality. This complication of lung disease is complex in its origin and carries a unique set of diagnostic and therapeutic issues. This review attempts to provide an overview of mechanisms associated with the onset of pulmonary hypertension in COPD and IPF, touches on appropriate evaluation, and reviews the state of knowledge on treating pulmonary hypertension related to underlying lung disease.
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Affiliation(s)
- Michael J Cuttica
- Northwestern Pulmonary Hypertension Program, 676 St Claire Suite 1400, Chicago, IL, 60611, USA.
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24
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Endothelial Cdc42 deficiency impairs endothelial regeneration and vascular repair after inflammatory vascular injury. Respir Res 2018; 19:27. [PMID: 29422044 PMCID: PMC5806471 DOI: 10.1186/s12931-018-0729-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 01/26/2018] [Indexed: 01/11/2023] Open
Abstract
Background Endothelial cell (EC) regeneration is essential for inflammation resolution and vascular integrity recovery after inflammatory vascular injury. Cdc42 is a central regulator of cell survival and vessel formation in EC development. However, it is unknown that whether Cdc42 could be a regulating role of EC repair following the inflammatory injury in the lung. The study sought to test the hypothesis that Cdc42 is required for endothelial regeneration and vascular integrity recovery after LPS-induced inflammatory injury. Methods and results The role of Cdc42 for the regulation of pulmonary vascular endothelial repair was tested in vitro and in vivo. In LPS-induced acute lung injury (ALI) mouse models, knockout of the Cdc42 gene in ECs increased inflammatory cell infiltration and pulmonary vascular leakage and inhibited vascular EC proliferation, which eventually resulted in more severe inflammatory lung injury. In addition, siRNA-mediated knockdown of Cdc42 protein on ECs disrupted cell proliferation and migration and tube formation, which are necessary processes for recovery after inflammatory vascular injury, resulting in inflammatory vascular injury recovery defects. Conclusion We found that Cdc42 deficiency impairs EC function and regeneration, which are crucial in the post-inflammatory vascular injury repair process. These findings indicate that Cdc42 is a potential target for novel treatments designed to facilitate endothelial regeneration and vascular repair in inflammatory pulmonary vascular diseases, such as ALI/ARDS. Electronic supplementary material The online version of this article (10.1186/s12931-018-0729-8) contains supplementary material, which is available to authorized users.
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25
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Kropski JA, Richmond BW, Gaskill CF, Foronjy RF, Majka SM. Deregulated angiogenesis in chronic lung diseases: a possible role for lung mesenchymal progenitor cells (2017 Grover Conference Series). Pulm Circ 2017; 8:2045893217739807. [PMID: 29040010 PMCID: PMC5731726 DOI: 10.1177/2045893217739807] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Chronic lung disease (CLD), including pulmonary fibrosis (PF) and chronic obstructive pulmonary disease (COPD), is the fourth leading cause of mortality worldwide. Both are debilitating pathologies that impede overall tissue function. A common co-morbidity in CLD is vasculopathy, characterized by deregulated angiogenesis, remodeling, and loss of microvessels. This substantially worsens prognosis and limits survival, with most current therapeutic strategies being largely palliative. The relevance of angiogenesis, both capillary and lymph, to the pathophysiology of CLD has not been resolved as conflicting evidence depicts angiogenesis as both reparative or pathologic. Therefore, we must begin to understand and model the underlying pathobiology of pulmonary vascular deregulation, alone and in response to injury induced disease, to define cell interactions necessary to maintain normal function and promote repair. Capillary and lymphangiogenesis are deregulated in both PF and COPD, although the mechanisms by which they co-regulate and underlie early pathogenesis of disease are unknown. The cell-specific mechanisms that regulate lung vascular homeostasis, repair, and remodeling represent a significant gap in knowledge, which presents an opportunity to develop targeted therapies. We have shown that that ABCG2pos multipotent adult mesenchymal stem or progenitor cells (MPC) influence the function of the capillary microvasculature as well as lymphangiogenesis. A balance of both is required for normal tissue homeostasis and repair. Our current models suggest that when lymph and capillary angiogenesis are out of balance, the non-equivalence appears to support the progression of disease and tissue remodeling. The angiogenic regulatory mechanisms underlying CLD likely impact other interstitial lung diseases, tuberous sclerosis, and lymphangioleiomyomatosis.
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Affiliation(s)
- Jonathan A Kropski
- 1 12328 Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Bradley W Richmond
- 1 12328 Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Christa F Gaskill
- 1 12328 Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Robert F Foronjy
- 3 5718 Department of Medicine, Vanderbilt University, Nashville, TN, USA
| | - Susan M Majka
- 1 12328 Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.,2 74498 Department of Medicine, Division of Pulmonary and Critical Care Medicine, SUNY Downstate Medical Center, Brooklyn, NY, USA
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26
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Suzuki T, Carrier EJ, Talati MH, Rathinasabapathy A, Chen X, Nishimura R, Tada Y, Tatsumi K, West J. Isolation and characterization of endothelial-to-mesenchymal transition cells in pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 2017; 314:L118-L126. [PMID: 28935639 DOI: 10.1152/ajplung.00296.2017] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Endothelial-to-mesenchymal transition (EndMT) is a process in which endothelial cells lose polarity and cell-to cell contacts, and undergo a dramatic remodeling of the cytoskeleton. It has been implicated in initiation and progression of pulmonary arterial hypertension (PAH). However, the characteristics of cells which have undergone EndMT cells in vivo have not been reported and so remain unclear. To study this, sugen5416 and hypoxia (SuHx)-induced PAH was established in Cdh5-Cre/Gt(ROSA)26Sortm4(ACTB-tdTomato,EGFP)Luo/J double transgenic mice, in which GFP was stably expressed in pan-endothelial cells. After 3 wk of SuHx, flow cytometry and immunohistochemistry demonstrated CD144-negative and GFP-positive cells (complete EndMT cells) possessed higher proliferative and migratory activity compared with other mesenchymal cells. While CD144-positive and α-smooth muscle actin (α-SMA)-positive cells (partial EndMT cells) continued to express endothelial progenitor cell markers, complete EndMT cells were Sca-1-rich mesenchymal cells with high proliferative and migratory ability. When transferred in fibronectin-coated chamber slides containing smooth muscle media, α-SMA robustly expressed in these cells compared with cEndMT cells that were grown in maintenance media. Demonstrating additional paracrine effects, conditioned medium from isolated complete EndMT cells induced enhanced mesenchymal proliferation and migration and increased angiogenesis compared with conditioned medium from resident mesenchymal cells. Overall, these findings show that EndMT cells could contribute to the pathogenesis of PAH both directly, by transformation into smooth muscle-like cells with higher proliferative and migratory potency, and indirectly, through paracrine effects on vascular intimal and medial proliferation.
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Affiliation(s)
- Toshio Suzuki
- Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center , Nashville, Tennessee.,Department of Respirology, Graduate School of Medicine, Chiba University , Chiba , Japan
| | - Erica J Carrier
- Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center , Nashville, Tennessee
| | - Megha H Talati
- Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center , Nashville, Tennessee
| | - Anandharajan Rathinasabapathy
- Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center , Nashville, Tennessee
| | - Xinping Chen
- Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center , Nashville, Tennessee
| | - Rintaro Nishimura
- Department of Respirology, Graduate School of Medicine, Chiba University , Chiba , Japan.,Department of Advanced Medicine in Pulmonary Hypertension, Graduate School of Medicine, Chiba University , Chiba , Japan
| | - Yuji Tada
- Department of Respirology, Graduate School of Medicine, Chiba University , Chiba , Japan
| | - Koichiro Tatsumi
- Department of Respirology, Graduate School of Medicine, Chiba University , Chiba , Japan
| | - James West
- Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center , Nashville, Tennessee
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27
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Wang D, Liu Y, Chen L, Li P, Qu Y, Zhu Y, Zhu Y. Key role of 15-LO/15-HETE in angiogenesis and functional recovery in later stages of post-stroke mice. Sci Rep 2017; 7:46698. [PMID: 28436420 PMCID: PMC5402258 DOI: 10.1038/srep46698] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Accepted: 03/21/2017] [Indexed: 02/08/2023] Open
Abstract
This study sought to clarify the effects of 15-lipoxygenase/15-hydroxyeicosatetraenoic acid in angiogenesis and neurological functional recovery after cerebral ischaemic stroke in mice. In vivo, we performed behavioural tests to determine functional recovery after stroke. Double immunofluorescence staining of CD31 and Ki67/PCNA was performed to evaluate the effects of 15-lipoxygenase/15-hydroxyeicosatetraenoic acid on angiogenesis in an MCAO mouse model. In vitro, we investigated the effects of 15-hydroxyeicosatetraenoic acid on BMVEC proliferation and migration. Our results show that MCAO upregulates 15-lipoxygenase expression in a time-dependent manner, especially in later stages of post-stroke. We confirmed that cerebral infarct area was reduced and neurological dysfunction was gradually attenuated after stroke, while 12/15-lipoxygenase knockout mice exhibited the opposite effects. Furthermore, immunofluorescence studies revealed 15-lipoxygenase increased the proliferation of mouse brain vascular endothelial cells in a time-dependent manner, while 12/15-lipoxygenase knockout blocked these effects. Moreover, 15-hydroxyeicosatetraenoic acid promoted proliferation and tube formation in BMVECs. These results demonstrate positive influence of 15-lipoxygenase/15-hydroxyeicosatetraenoic acid in angiogenesis and neuronal recovery after ischaemic stroke in mice. We also confirmed the PI3K/Akt signalling pathway was necessary for the effects of 15-hydroxyeicosatetraenoic acid in regulation of BMVEC proliferation and migration, which may potentially be a novel target for the recovery from ischaemic stroke.
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Affiliation(s)
- Di Wang
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, Heilongjiang 150086, China
| | - Yu Liu
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, Heilongjiang 150086, China
| | - Li Chen
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, Heilongjiang 150086, China
| | - Pengyan Li
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, Heilongjiang 150086, China
| | - Youyang Qu
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, Heilongjiang 150086, China
| | - Yanmei Zhu
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, Heilongjiang 150086, China
| | - Yulan Zhu
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, Heilongjiang 150086, China
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28
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Wang L, Xu Z, Chen B, He W, Hu J, Zhang L, Liu X, Chen F. The Role of Vascular Endothelial Growth Factor in Small-airway Remodelling in a Rat Model of Chronic Obstructive Pulmonary Disease. Sci Rep 2017; 7:41202. [PMID: 28117425 PMCID: PMC5259712 DOI: 10.1038/srep41202] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 12/16/2016] [Indexed: 11/08/2022] Open
Abstract
Small-airway remodelling is one of the most remarkable pathological features of chronic obstructive pulmonary disease (COPD), in which angiogenesis plays a critical role that contributes to disease progression. The endothelial cell-specific mitogen vascular endothelial growth factor (VEGF), as well as its receptors, VEGFR1, VEGFR2, are thought to be the major mediators of pathological angiogenesis, and sunitinib exhibits anti-angiogenesis property through VEGF blockage and has been widely used to treat various cancers. In our study, Sprague-Dawley rats were subjected to lipopolysaccharide (LPS) injection and cigarette smoke (CS) inhalation to induce COPD, following sunitinib administration was conducted. Haematoxylin-eosin, Masson staining and immunostaining analysis were used to evaluate the pathological changes; quantitative real-time PCR and enzyme-linked immunosorbent assay were performed to provide more compelling data on the function of VEGF, VEGFR1, VEGFR2 in angiogenesis. Sunitinib treatment was associated with less angiogenesis in small-airway remodelling with a slightly disordered lung architecture, and lower expression level of VEGF, VEGFR1, VEGFR2. Overall, our results indicate that VEGF is a vital important factor that contributes to the small-airway remodelling in a rat model of COPD through promoting angiogenesis, which mainly depend on the specific binding between VEGF and VEGFR1 and can be effectively attenuated by sunitinib.
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Affiliation(s)
- Lu Wang
- Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Zhibo Xu
- Department of respiration, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006, People’s Republic of China
| | - Bin Chen
- Respiratory physiology Laboratory, The First Affiliated Hospital of Zhejiang Chinese Medical University, 310006, People’s Republic of China
| | - Wei He
- Department of respiration, Shaoxing Hospital of Traditional Chinese Medicine, Shaoxing, 312000, People’s Republic of China
| | - Jingxian Hu
- Department of respiration, Dongyang Hospital of Traditional Chinese Medicine, Jinhua, 322100, People’s Republic of China
| | - Liting Zhang
- Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Xianzhong Liu
- Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Fang Chen
- Respiratory physiology Laboratory, The First Affiliated Hospital of Zhejiang Chinese Medical University, 310006, People’s Republic of China
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29
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Lv J, Zeng J, Zhao W, Cheng Y, Zhang L, Cai S, Hu G, Chen Y. Cdc42 regulates LPS-induced proliferation of primary pulmonary microvascular endothelial cells via ERK pathway. Microvasc Res 2016; 109:45-53. [PMID: 27769693 DOI: 10.1016/j.mvr.2016.10.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Revised: 09/21/2016] [Accepted: 10/17/2016] [Indexed: 12/17/2022]
Abstract
BACKGROUND After stimulation due to injury, cell division cycle protein 42 (Cdc42) restores and enhances barrier functions by strengthening intercellular adherens junctions; however, its influence on cell proliferation after injury remains unknown. OBJECTIVE In this study, we sought to investigate the effect of stimulation using small doses of lipopolysaccharide (LPS) on the proliferation of pulmonary microvascular endothelial cells (PMVECs). METHODS We stimulated PMVECs with different doses of LPS and evaluated the effects on cell proliferation. We also constructed a primary gene-knockout cell line lacking Cdc42 to verify the role of Cdc42 in regulating the proliferation of PMVECs that were stimulated using LPS and to explore related signaling pathways. RESULTS Stimulating PMVECs with small doses of LPS increased proliferation. Cdc42 is involved in regulating this process, which was mediated by the extracellular regulated protein kinase (ERK) pathway. CONCLUSIONS Cdc42 plays a role in regulating the proliferation of PMVECs stimulated with small doses of LPS, and this regulation involves the ERK pathway.
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Affiliation(s)
- Jiawen Lv
- Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Junchao Zeng
- Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Wen Zhao
- Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yuanxiong Cheng
- Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Lin Zhang
- Department of Histology and Embryology, School of Basic Medical Sciences Southern Medical University, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Guangzhou 510515, China
| | - Shaoxi Cai
- Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Guodong Hu
- Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
| | - Yinghua Chen
- Department of Histology and Embryology, School of Basic Medical Sciences Southern Medical University, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Guangzhou 510515, China.
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30
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Phillips MR, Moore SM, Shah M, Lee C, Lee YZ, Faber JE, McLean SE. A method for evaluating the murine pulmonary vasculature using micro-computed tomography. J Surg Res 2016; 207:115-122. [PMID: 27979466 DOI: 10.1016/j.jss.2016.08.074] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 08/05/2016] [Accepted: 08/24/2016] [Indexed: 01/04/2023]
Abstract
BACKGROUND Significant mortality and morbidity are associated with alterations in the pulmonary vasculature. While techniques have been described for quantitative morphometry of whole-lung arterial trees in larger animals, no methods have been described in mice. We report a method for the quantitative assessment of murine pulmonary arterial vasculature using high-resolution computed tomography scanning. METHODS Mice were harvested at 2 weeks, 4 weeks, and 3 months of age. The pulmonary artery vascular tree was pressure perfused to maximal dilation with a radio-opaque casting material with viscosity and pressure set to prevent capillary transit and venous filling. The lungs were fixed and scanned on a specimen computed tomography scanner at 8-μm resolution, and the vessels were segmented. Vessels were grouped into categories based on lumen diameter and branch generation. RESULTS Robust high-resolution segmentation was achieved, permitting detailed quantitation of pulmonary vascular morphometrics. As expected, postnatal lung development was associated with progressive increase in small-vessel number and arterial branching complexity. CONCLUSIONS These methods for quantitative analysis of the pulmonary vasculature in postnatal and adult mice provide a useful tool for the evaluation of mouse models of disease that affect the pulmonary vasculature.
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Affiliation(s)
- Michael R Phillips
- Division of Pediatric Surgery, Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Scott M Moore
- Division of Pediatric Surgery, Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Mansi Shah
- Division of Pediatric Surgery, Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Clara Lee
- Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Yueh Z Lee
- Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - James E Faber
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Sean E McLean
- Division of Pediatric Surgery, Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
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31
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Kim SY, Kim HJ, Park MK, Huh JW, Park HY, Ha SY, Shin JH, Lee YS. Mitochondrial E3 Ubiquitin Protein Ligase 1 Mediates Cigarette Smoke-Induced Endothelial Cell Death and Dysfunction. Am J Respir Cell Mol Biol 2016. [PMID: 26203915 DOI: 10.1165/rcmb.2014-0377oc] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
By virtue of the critical roles of Akt in vascular endothelial cell (EC) survival and function, cigarette smoke-induced Akt reduction may contribute to EC death and dysfunction in smokers' lungs. One of the negative Akt regulatory mechanisms is K48-linked Akt ubiquitination and subsequent proteasomal degradation. Here, we assessed the involvement of mitochondrial E3 ubiquitin protein ligase 1 (MUL1), recently revealed as a novel Akt ubiquitin E3 ligase, in cigarette smoke-induced Akt ubiquitination and its contribution to pulmonary EC death and dysfunction. In human lung microvascular ECs (HLMVECs), cigarette smoke extract (CSE) noticeably elevated MUL1 expression and K48-linked Akt ubiquitination, whereas Akt, p-Akt, eNOS, and p-eNOS levels were decreased. MUL1 knockdown suppressed CSE-induced Akt ubiquitination/degradation and cytoplasmic reductions of Akt and p-Akt. Furthermore, MUL1 knockdown attenuated reductions of eNOS and p-eNOS and alleviated EC survival, migration, and tube formation in the presence of CSE exposure. In addition, overexpression of K284R Akt, a mutant for a MUL1-ubiquitination site, produced similar effects. In HLMVECs exposed to CSE, Akt-MUL1 interaction was increased in coimmunoprecipitation and in situ proximity ligation assays. Similarly, the proximity ligation assay signals were elevated in rat lungs exposed to cigarette smoke for 3 months, during which Mul1 levels were noticeably increased. Finally, we found that CSE-mediated MUL1 induction in HLMVECs is mediated by retinoic acid receptor-related orphan receptor α. Taken together, these data suggest that cigarette smoke-induced MUL1 elevation mediates Akt ubiquitination/degradation, potentially leading to pulmonary EC death and functional impairment.
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Affiliation(s)
- Sun-Yong Kim
- 1 Department of Otolaryngology, Ajou University School of Medicine, Suwon
| | - Hyo Jeong Kim
- 2 Department of Pharmacology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon
| | - Mi Kyeong Park
- 2 Department of Pharmacology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon
| | - Jin Won Huh
- 3 Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul; and
| | - Hye Yun Park
- 4 Division of Pulmonary and Critical Care Medicine, Department of Medicine and
| | - Sang Yun Ha
- 5 Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Joo-Ho Shin
- 2 Department of Pharmacology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon
| | - Yun-Song Lee
- 2 Department of Pharmacology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon
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32
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White ES. Commentary: A Breath of Fresh Air on the Mesenchyme: Impact of Impaired Mesenchymal Development on the Pathogenesis of Bronchopulmonary Dysplasia. Front Med (Lausanne) 2016; 3:13. [PMID: 27066487 PMCID: PMC4815635 DOI: 10.3389/fmed.2016.00013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Accepted: 03/24/2016] [Indexed: 11/25/2022] Open
Affiliation(s)
- Eric S White
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School , Ann Arbor, MI , USA
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33
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Li J, Zhang L, Zhang Y, Liu Y, Zhang H, Wei L, Shen T, Jiang C, Zhu D. A20 deficiency leads to angiogenesis of pulmonary artery endothelial cells through stronger NF-κB activation under hypoxia. J Cell Mol Med 2016; 20:1319-28. [PMID: 26991692 PMCID: PMC4929300 DOI: 10.1111/jcmm.12816] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 01/17/2016] [Indexed: 12/11/2022] Open
Abstract
A20 is a zinc finger protein associated with hypoxia. As chronic hypoxia is responsible for intimal hyperplasia and disordered angiogenesis of pulmonary artery, which are histological hallmarks of pulmonary artery hypertension, we intended to explore the role of A20 in angiogenesis of pulmonary artery endothelial cells (ECs). Here, we found a transient elevation of A20 expression in the lung tissues from hypoxic rats compared with normoxic controls. This rapid enhancement was mainly detected in the endothelium, and similar results were reproduced in vitro. During early hypoxia, genetic inhibition of A20 increased proliferation in pulmonary artery ECs, linking to advanced cell cycle progression as well as microtubule polymerization, and aggravated angiogenic effects including tube formation, cell migration and adhesion molecules expression. In addition, a negative feedback loop between nuclear factor-kappa B and A20 was confirmed. Our findings provide evidence for an adaptive role of A20 against pulmonary artery ECs angiogenesis via nuclear factor-kappa B activation.
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Affiliation(s)
- Jing Li
- Department of Biopharmaceutical Sciences, Harbin Medical University, Daqing, Heilongjiang, China.,Department of Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin Medical University, Harbin, Heilongjiang, China
| | - Linlin Zhang
- Department of Biopharmaceutical Sciences, Harbin Medical University, Daqing, Heilongjiang, China
| | - Yueming Zhang
- Department of Biopharmaceutical Sciences, Harbin Medical University, Daqing, Heilongjiang, China.,Department of Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin Medical University, Harbin, Heilongjiang, China
| | - Ying Liu
- Department of Biopharmaceutical Sciences, Harbin Medical University, Daqing, Heilongjiang, China.,Department of Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin Medical University, Harbin, Heilongjiang, China
| | - Hongyue Zhang
- Department of Biopharmaceutical Sciences, Harbin Medical University, Daqing, Heilongjiang, China.,Department of Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin Medical University, Harbin, Heilongjiang, China
| | - Liuping Wei
- Department of Biopharmaceutical Sciences, Harbin Medical University, Daqing, Heilongjiang, China.,Department of Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin Medical University, Harbin, Heilongjiang, China
| | - Tingting Shen
- Department of Biopharmaceutical Sciences, Harbin Medical University, Daqing, Heilongjiang, China.,Department of Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin Medical University, Harbin, Heilongjiang, China
| | - Chun Jiang
- Department of Biology, Georgia State University, Atlanta, GA, USA
| | - Daling Zhu
- Department of Biopharmaceutical Sciences, Harbin Medical University, Daqing, Heilongjiang, China.,Department of Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin Medical University, Harbin, Heilongjiang, China
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Spartalis E, Tomos P, Moris D, Athanasiou A, Markakis C, Spartalis MD, Troupis T, Dimitroulis D, Perrea D. Role of platelet-rich plasma in ischemic heart disease: An update on the latest evidence. World J Cardiol 2015; 7:665-670. [PMID: 26516421 PMCID: PMC4620078 DOI: 10.4330/wjc.v7.i10.665] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Revised: 07/07/2015] [Accepted: 09/08/2015] [Indexed: 02/06/2023] Open
Abstract
Myocardial infarction is the most common cause of congestive heart failure. Novel strategies such as directly reprogramming cardiac fibroblasts into cardiomyocytes are an exciting area of investigation for repair of injured myocardial tissue. The ultimate goal is to rebuild functional myocardium by transplanting exogenous stem cells or by activating native stem cells to induce endogenous repair. Cell-based myocardial restoration, however, has not penetrated broad clinical practice yet. Platelet-rich plasma, an autologous fractionation of whole blood containing high concentrations of growth factors, has been shown to safely and effectively enhance healing and angiogenesis primarily by reparative cell signaling. In this review, we collected all recent advances in novel therapies as well as experimental evidence demonstrating the role of platelet-rich plasma in ischemic heart disease, focusing on aspects that might be important for future successful clinical application.
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The isolation and culture of endothelial colony-forming cells from human and rat lungs. Nat Protoc 2015; 10:1697-708. [DOI: 10.1038/nprot.2015.107] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
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Ali AA, Abd El-Aziz AA, El Wahsh RA, El-Shafie MK, Heweet SA. Serum Angiopoietin-2 and C-reactive protein as biomarkers of acute exacerbations of chronic obstructive pulmonary diseases. EGYPTIAN JOURNAL OF CHEST DISEASES AND TUBERCULOSIS 2015. [DOI: 10.1016/j.ejcdt.2014.11.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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Mammoto T, Mammoto A. Implantation of fibrin gel on mouse lung to study lung-specific angiogenesis. J Vis Exp 2014:52012. [PMID: 25548859 PMCID: PMC4396947 DOI: 10.3791/52012] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Recent significant advances in stem cell research and bioengineering techniques have made great progress in utilizing biomaterials to regenerate and repair damage in simple tissues in the orthopedic and periodontal fields. However, attempts to regenerate the structures and functions of more complex three-dimensional (3D) organs such as lungs have not been very successful because the biological processes of organ regeneration have not been well explored. It is becoming clear that angiogenesis, the formation of new blood vessels, plays key roles in organ regeneration. Newly formed vasculatures not only deliver oxygen, nutrients and various cell components that are required for organ regeneration but also provide instructive signals to the regenerating local tissues. Therefore, to successfully regenerate lungs in an adult, it is necessary to recapitulate the lung-specific microenvironments in which angiogenesis drives regeneration of local lung tissues. Although conventional in vivo angiogenesis assays, such as subcutaneous implantation of extracellular matrix (ECM)-rich hydrogels (e.g., fibrin or collagen gels or Matrigel - ECM protein mixture secreted by Engelbreth-Holm-Swarm mouse sarcoma cells), are extensively utilized to explore the general mechanisms of angiogenesis, lung-specific angiogenesis has not been well characterized because methods for orthotopic implantation of biomaterials in the lung have not been well established. The goal of this protocol is to introduce a unique method to implant fibrin gel on the lung surface of living adult mouse, allowing for the successful recapitulation of host lung-derived angiogenesis inside the gel. This approach enables researchers to explore the mechanisms by which the lung-specific microenvironment controls angiogenesis and alveolar regeneration in both normal and pathological conditions. Since implanted biomaterials release and supply physical and chemical signals to adjacent lung tissues, implantation of these biomaterials on diseased lung can potentially normalize the adjacent diseased tissues, enabling researchers to develop new therapeutic approaches for various types of lung diseases.
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Affiliation(s)
- Tadanori Mammoto
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital and Harvard Medical School;
| | - Akiko Mammoto
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital and Harvard Medical School;
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Abstract
Chronic obstructive pulmonary disorder (COPD) is a systemic disease that affects the cardiovascular system through multiple pathways. Pulmonary hypertension, ventricular dysfunction, and atherosclerosis are associated with smoking and COPD, causing significant morbidity and poor prognosis. Coupling between the pulmonary and cardiovascular system involves mechanical interdependence and inflammatory pathways that potentially affect the entire circulation. Although treatments specific for COPD-related cardiovascular and pulmonary vascular disease are limited, early diagnosis, study of pathophysiology, and monitoring the effects of treatment are enhanced with improved imaging techniques. In this article, we review recent advancements in the imaging of the vasculature and the heart in patients with COPD. We also explore the potential mechanism of coupling between the progression of COPD and vascular disease. Imaging methods reviewed include specific implementations of computed tomography, magnetic resonance imaging, dual-energy computed tomography, positron emission tomography, and echocardiography. Specific applications to the proximal and distal pulmonary vasculature, as well as to the heart and systemic circulation, are also discussed.
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Vuong B, Lee AMD, Luk TWH, Sun C, Lam S, Lane P, Yang VXD. High speed, wide velocity dynamic range Doppler optical coherence tomography (Part IV): split spectrum processing in rotary catheter probes. OPTICS EXPRESS 2014; 22:7399-415. [PMID: 24718115 DOI: 10.1364/oe.22.007399] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
We report a technique for blood flow detection using split spectrum Doppler optical coherence tomography (ssDOCT) that shows improved sensitivity over existing Doppler OCT methods. In ssDOCT, the Doppler signal is averaged over multiple sub-bands of the interferogram, increasing the SNR of the Doppler signal. We explore the parameterization of this technique in terms of number of sub-band windows, width and overlap of the windows, and their effect on the Doppler signal to noise in a flow phantom. Compared to conventional DOCT, ssDOCT processing has increased flow sensitivity. We demonstrate the effectiveness of ssDOCT in-vivo for intravascular flow detection within a porcine carotid artery and for microvascular vessel detection in human pulmonary imaging, using rotary catheter probes. To our knowledge, this is the first report of visualizing in-vivo Doppler flow patterns adjacent to stent struts in the carotid artery.
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McLoughlin P, Keane MP. Physiological and pathological angiogenesis in the adult pulmonary circulation. Compr Physiol 2013; 1:1473-508. [PMID: 23733650 DOI: 10.1002/cphy.c100034] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Angiogenesis occurs during growth and physiological adaptation in many systemic organs, for example, exercise-induced skeletal and cardiac muscle hypertrophy, ovulation, and tissue repair. Disordered angiogenesis contributes to chronic inflammatory disease processes and to tumor growth and metastasis. Although it was previously thought that the adult pulmonary circulation was incapable of supporting new vessel growth, over that past 10 years new data have shown that angiogenesis within this circulation occurs both during physiological adaptive processes and as part of the pathogenic mechanisms of lung diseases. Here we review the expression of vascular growth factors in the adult lung, their essential role in pulmonary vascular homeostasis and the changes in their expression that occur in response to physiological challenges and in disease. We consider the evidence for adaptive neovascularization in the pulmonary circulation in response to alveolar hypoxia and during lung growth following pneumonectomy in the adult lung. In addition, we review the role of disordered angiogenesis in specific lung diseases including idiopathic pulmonary fibrosis, acute adult distress syndrome and both primary and metastatic tumors of the lung. Finally, we examine recent experimental data showing that therapeutic enhancement of pulmonary angiogenesis has the potential to treat lung diseases characterized by vessel loss.
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Affiliation(s)
- Paul McLoughlin
- University College Dublin, School of Medicine and Medical Sciences, Conway Institute, and St. Vincent's University Hospital, Dublin, Ireland.
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41
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Basile DP, Yoder MC. Circulating and tissue resident endothelial progenitor cells. J Cell Physiol 2013; 229:10-6. [PMID: 23794280 DOI: 10.1002/jcp.24423] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Accepted: 06/17/2013] [Indexed: 12/31/2022]
Abstract
Progenitor cells for the endothelial lineage have been widely investigated for more than a decade, but continue to be controversial since no unique identifying marker has yet been identified. This review will begin with a discussion of the basic tenets originally proposed for proof that a cell displays properties of an endothelial progenitor cell. We then provide an overview of the methods for putative endothelial progenitor cell derivation, expansion, and enumeration. This discussion includes consideration of cells that are present in the circulation as well as cells resident in the vascular endothelial intima. Finally, we provide some suggested changes in nomenclature that would greatly clarify and demystify the cellular elements involved in vascular repair.
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Affiliation(s)
- David P Basile
- Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana
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Magkrioti C, Aidinis V. Autotaxin and lysophosphatidic acid signalling in lung pathophysiology. World J Respirol 2013; 3:77-103. [DOI: 10.5320/wjr.v3.i3.77] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2013] [Revised: 10/03/2013] [Accepted: 11/19/2013] [Indexed: 02/06/2023] Open
Abstract
Autotaxin (ATX or ENPP2) is a secreted glycoprotein widely present in biological fluids. ATX primarily functions as a plasma lysophospholipase D and is largely responsible for the bulk of lysophosphatidic acid (LPA) production in the plasma and at inflamed and/or malignant sites. LPA is a phospholipid mediator produced in various conditions both in cells and in biological fluids, and it evokes growth-factor-like responses, including cell growth, survival, differentiation and motility, in almost all cell types. The large variety of LPA effector functions is attributed to at least six G-protein coupled LPA receptors (LPARs) with overlapping specificities and widespread distribution. Increased ATX/LPA/LPAR levels have been detected in a large variety of cancers and transformed cell lines, as well as in non-malignant inflamed tissues, suggesting a possible involvement of ATX in chronic inflammatory disorders and cancer. In this review, we focus exclusively on the role of the ATX/LPA axis in pulmonary pathophysiology, analysing the effects of ATX/LPA on pulmonary cells and leukocytes in vitro and in the context of pulmonary pathophysiological situations in vivo and in human diseases.
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Lactate dehydrogenase a expression is necessary to sustain rapid angiogenesis of pulmonary microvascular endothelium. PLoS One 2013; 8:e75984. [PMID: 24086675 PMCID: PMC3784391 DOI: 10.1371/journal.pone.0075984] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 08/19/2013] [Indexed: 01/11/2023] Open
Abstract
Angiogenesis is a fundamental property of endothelium, yet not all endothelial cells display equivalent angiogenic responses; pulmonary microvascular endothelial cells undergo rapid angiogenesis when compared to endothelial cells isolated from conduit vessels. At present it is not clear how pulmonary microvascular endothelial cells fulfill the bioenergetic demands that are necessary to sustain such rapid blood vessel formation. We have previously established that pulmonary microvascular endothelial cells utilize aerobic glycolysis to generate ATP during growth, a process that requires the expression of lactate dehydrogenase A to convert pyruvate to lactate. Here, we test the hypothesis that lactate dehydrogenase A is required for pulmonary microvascular endothelial cells to sustain rapid angiogenesis. To test this hypothesis, Tet-On and Tet-Off conditional expression systems were developed in pulmonary microvascular endothelial cells, where doxycycline is utilized to induce lactate dehydrogenase A shRNA expression. Expression of LDH-A shRNA induced a time-dependent decrease in LDH-A protein, which corresponded with a decrease in glucose consumption from the media, lactate production and cell growth; re-expression of LDH-A rescued each of these parameters. LDH-A silencing greatly reduced network formation on Matrigel in vitro, and decreased blood vessel formation in Matrigel in vivo. These findings demonstrate that LDH-A is critically important for sustaining the rapid angiogenesis of pulmonary microvascular endothelial cells.
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Mammoto T, Jiang E, Jiang A, Lu Y, Juan AM, Chen J, Mammoto A. Twist1 controls lung vascular permeability and endotoxin-induced pulmonary edema by altering Tie2 expression. PLoS One 2013; 8:e73407. [PMID: 24023872 PMCID: PMC3759405 DOI: 10.1371/journal.pone.0073407] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2013] [Accepted: 07/20/2013] [Indexed: 11/19/2022] Open
Abstract
Tight regulation of vascular permeability is necessary for normal development and deregulated vascular barrier function contributes to the pathogenesis of various diseases, including acute respiratory distress syndrome, cancer and inflammation. The angiopoietin (Ang)-Tie2 pathway is known to control vascular permeability. However, the mechanism by which the expression of Tie2 is regulated to control vascular permeability has not been fully elucidated. Here we show that transcription factor Twist1 modulates pulmonary vascular leakage by altering the expression of Tie2 in a context-dependent way. Twist1 knockdown in cultured human lung microvascular endothelial cells decreases Tie2 expression and phosphorylation and increases RhoA activity, which disrupts cell-cell junctional integrity and increases vascular permeability in vitro. In physiological conditions, where Ang1 is dominant, pulmonary vascular permeability is elevated in the Tie2-specific Twist1 knockout mice. However, depletion of Twist1 and resultant suppression of Tie2 expression prevent increase in vascular permeability in an endotoxin-induced lung injury model, where the balance of Angs shifts toward Ang2. These results suggest that Twist1-Tie2-Angs signaling is important for controlling vascular permeability and modulation of this mechanism may lead to the development of new therapeutic approaches for pulmonary edema and other diseases caused by abnormal vascular permeability.
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Affiliation(s)
- Tadanori Mammoto
- 1 Vascular Biology Program, Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Elisabeth Jiang
- 1 Vascular Biology Program, Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Amanda Jiang
- 1 Vascular Biology Program, Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Yongbo Lu
- 2 Department of Biomedical Sciences, Baylor College of Dentistry, Texas A&M Health Science Center, Dallas, Texas, United States of America
| | - Aimee M. Juan
- 3 Department of Ophthalmology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Jing Chen
- 3 Department of Ophthalmology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Akiko Mammoto
- 1 Vascular Biology Program, Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
- * E-mail:
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Ma C, Wang Y, Shen T, Zhang C, Ma J, Zhang L, Liu F, Zhu D. Placenta growth factor mediates angiogenesis in hypoxic pulmonary hypertension. Prostaglandins Leukot Essent Fatty Acids 2013; 89:159-68. [PMID: 24001991 DOI: 10.1016/j.plefa.2013.08.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2012] [Revised: 06/10/2013] [Accepted: 08/10/2013] [Indexed: 12/21/2022]
Abstract
Our previous studies have proved that hypoxia enhances the 15-lipoxygenase (15-LO) expression and increases endogenous 15-hydroxyeicosatetraenoic acid (15-HETE) production to promote pulmonary vascular remodeling and angiogenesis, while the mechanisms of how hypoxia regulates 15-LO expression in endothelium is still unknown. As placenta growth factor (PlGF) promotes pathological angiogenesis by acting on the growth, migration and survival of endothelial cells, there may be some connections between PlGF and 15-LO in hypoxia induced endothelial cells proliferation. In this study, we performed immunohistochemistry, pulmonary artery endothelial cells migration and bromodeoxyuridine incorporation to determine the role of PlGF in pulmonary remodeling induced by hypoxia. Our results showed that hypoxia up-regulated PlGF expression, which was mediated by 15-LO/15-HETE pathway. Furthermore, we found that PlGF had a positive feedback regulation with 15-LO expression and 15-HETE generation. The interaction in hypoxia between 15-HETE and PlGF created a PlGF-15-LO-15-HETE loop, leading to endothelial dysfunction. Thus, these findings suggest a new therapeutic agent in combination with the blockade of PlGF as well as 15-LO in hypoxic pulmonary hypertension.
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Affiliation(s)
- Cui Ma
- Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University-Daqing, Daqing 163319, China
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Schmieder AH, Wang K, Zhang H, Senpan A, Pan D, Keupp J, Caruthers SD, Wickline SA, Shen B, Wagner EM, Lanza GM. Characterization of early neovascular response to acute lung ischemia using simultaneous (19)F/ (1)H MR molecular imaging. Angiogenesis 2013; 17:51-60. [PMID: 23918207 DOI: 10.1007/s10456-013-9377-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2013] [Accepted: 07/29/2013] [Indexed: 12/31/2022]
Abstract
Angiogenesis is an important constituent of many inflammatory pulmonary diseases, which has been unappreciated until recently. Early neovascular expansion in the lungs in preclinical models and patients is very difficult to assess noninvasively, particularly quantitatively. The present study demonstrated that (19)F/(1)H MR molecular imaging with αvβ3-targeted perfluorocarbon nanoparticles can be used to directly measure neovascularity in a rat left pulmonary artery ligation (LPAL) model, which was employed to create pulmonary ischemia and induce angiogenesis. In rats 3 days after LPAL, simultaneous (19)F/(1)H MR imaging at 3T revealed a marked (19)F signal in animals 2 h following αvβ3-targeted perfluorocarbon nanoparticles [(19)F signal (normalized to background) = 0.80 ± 0.2] that was greater (p = 0.007) than the non-targeted (0.30 ± 0.04) and the sham-operated (0.07 ± 0.09) control groups. Almost no (19)F signal was found in control right lung with any treatment. Competitive blockade of the integrin-targeted particles greatly decreased the (19)F signal (p = 0.002) and was equivalent to the non-targeted control group. Fluorescent and light microscopy illustrated heavy decorating of vessel walls in and around large bronchi and large pulmonary vessels. Focal segmental regions of neovessel expansion were also noted in the lung periphery. Our results demonstrate that (19)F/(1)H MR molecular imaging with αvβ3-targeted perfluorocarbon nanoparticles provides a means to assess the extent of systemic neovascularization in the lung.
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Affiliation(s)
- Anne H Schmieder
- Department of Medicine, Washington University School of Medicine, 660 S. Euclid, Campus Box 8215, St. Louis, MO, 63110, USA,
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Mammoto T, Jiang A, Jiang E, Mammoto A. Platelet rich plasma extract promotes angiogenesis through the angiopoietin1-Tie2 pathway. Microvasc Res 2013; 89:15-24. [PMID: 23660186 DOI: 10.1016/j.mvr.2013.04.008] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Revised: 04/23/2013] [Accepted: 04/28/2013] [Indexed: 12/18/2022]
Abstract
Development and regeneration of tissues and organs require precise coordination among endothelial, epithelial and mesenchymal morphogenesis. Angiogenesis plays key roles in normal development, wound healing, recovery from ischemic disease, and organ regeneration. It has been recognized that the combination of various angiogenic factors in an appropriate physiological ratio is critical for long-term functional blood vessel formation. Here we show that mouse soluble platelet-rich-plasma (PRP) extract, which includes abundant angiopoetin-1 (Ang1) and other angiogenic factors, stimulates endothelial cell growth, migration and differentiation in cultured human dermal microvascular endothelial cells in vitro and neonatal mouse retinal angiogenesis in vivo. Mouse platelet rich fibrin (PRF) matrix, the three-dimensional fibrin matrix that releases angiogenic factors with similar concentrations and proportions to the PRP extract, also recapitulates robust angiogenesis inside the matrix when implanted subcutaneously on the living mouse. Inhibition of Ang1-Tie2 signaling suppresses PRP extract-induced angiogenesis in vitro and angiogenic ability of the PRF matrix in vivo. Since human PRP extract and PRF matrix can be prepared from autologous peripheral blood, our findings may lead to the development of novel therapeutic interventions for various angiogenesis-related diseases as well as to the improvement of strategies for tissue engineering and organ regeneration.
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Affiliation(s)
- Tadanori Mammoto
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Boston, MA 02115, USA
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Iosef C, Alastalo TP, Hou Y, Chen C, Adams ES, Lyu SC, Cornfield DN, Alvira CM. Inhibiting NF-κB in the developing lung disrupts angiogenesis and alveolarization. Am J Physiol Lung Cell Mol Physiol 2012; 302:L1023-36. [PMID: 22367785 DOI: 10.1152/ajplung.00230.2011] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Bronchopulmonary dysplasia (BPD), a chronic lung disease of infancy, is characterized by arrested alveolar development. Pulmonary angiogenesis, mediated by the vascular endothelial growth factor (VEGF) pathway, is essential for alveolarization. However, the transcriptional regulators mediating pulmonary angiogenesis remain unknown. We previously demonstrated that NF-κB, a transcription factor traditionally associated with inflammation, plays a unique protective role in the neonatal lung. Therefore, we hypothesized that constitutive NF-κB activity is essential for postnatal lung development. Blocking NF-κB activity in 6-day-old neonatal mice induced the alveolar simplification similar to that observed in BPD and significantly reduced pulmonary capillary density. Studies to determine the mechanism responsible for this effect identified greater constitutive NF-κB in neonatal lung and in primary pulmonary endothelial cells (PEC) compared with adult. Moreover, inhibiting constitutive NF-κB activity in the neonatal PEC with either pharmacological inhibitors or RNA interference blocked PEC survival, decreased proliferation, and impaired in vitro angiogenesis. Finally, by chromatin immunoprecipitation, NF-κB was found to be a direct regulator of the angiogenic mediator, VEGF-receptor-2, in the neonatal pulmonary vasculature. Taken together, our data identify an entirely novel role for NF-κB in promoting physiological angiogenesis and alveolarization in the developing lung. Our data suggest that disruption of NF-κB signaling may contribute to the pathogenesis of BPD and that enhancement of NF-κB may represent a viable therapeutic strategy to promote lung growth and regeneration in pulmonary diseases marked by impaired angiogenesis.
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Affiliation(s)
- Cristiana Iosef
- Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, 300 Pasteur Dr., Stanford, CA 94305-5208, USA
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Thomson EM, Williams A, Yauk CL, Vincent R. Overexpression of tumor necrosis factor-α in the lungs alters immune response, matrix remodeling, and repair and maintenance pathways. THE AMERICAN JOURNAL OF PATHOLOGY 2012; 180:1413-30. [PMID: 22322299 DOI: 10.1016/j.ajpath.2011.12.020] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2011] [Revised: 12/03/2011] [Accepted: 12/09/2011] [Indexed: 11/25/2022]
Abstract
Increased production of tumor necrosis factor (TNF)-α and matrix metalloproteinases (MMPs) is a feature of inflammatory lung diseases, including emphysema and fibrosis, but the divergent pathological characteristics that result indicate involvement of other processes in disease pathogenesis. Transgenic mice overexpressing TNF-α in type II alveolar epithelial cells under the control of the surfactant protein (SP)-C promoter develop pulmonary inflammation and emphysema but are resistant to induction of fibrosis by administration of bleomycin or transforming growth factor-β. To study the molecular mechanisms underlying the development of this phenotype, we used a microarray approach to characterize the pulmonary transcriptome of SP-C/TNF-α mice and wild-type littermates. Four-month-old SP-C/TNF-α mice displayed pronounced pulmonary inflammation, airspace enlargement, increased MMP-2 and MMP-9 levels, and altered expression of 2332 probes. The functional assessment of genes with increased expression revealed enrichment of inflammatory/immune responses and proteases, whereas genes involved in protease inhibition, angiogenesis, cross-linking of basement membrane proteins, and myofibroblast differentiation were predominantly decreased. Comparison with multiple lung disease models identified a set of genes unique to the SP-C/TNF-α model and revealed that lack of extracellular matrix production distinguished SP-C/TNF-α mice from fibrosis models. Activation of inflammatory and proteolytic pathways and disruption of maintenance and repair processes are central features of emphysema in this TNF-overexpression model. Impairment of myofibroblast differentiation and extracellular matrix production may underlie resistance to induction of fibrosis.
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Affiliation(s)
- Errol M Thomson
- Hazard Identification Division, Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada.
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Chen L, Ackerman R, Guo AM. 20-HETE in neovascularization. Prostaglandins Other Lipid Mediat 2011; 98:63-8. [PMID: 22227460 DOI: 10.1016/j.prostaglandins.2011.12.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2011] [Revised: 12/09/2011] [Accepted: 12/19/2011] [Indexed: 12/18/2022]
Abstract
Cytochrome P450 4A/F (CYP4A/F) converts arachidonic acid (AA) to 20-HETE by ω-hydroxylation. The contribution of 20-HETE to the regulation of myogenic response, blood pressure, and mitogenic actions has been well summarized. This review focuses on the emerging role of 20-HETE in physiological and pathological vascularization. 20-HETE has been shown to regulate vascular smooth muscle cells (VSMC) and endothelial cells (EC) by affecting their proliferation, migration, survival, and tube formation. Furthermore, the proliferation, migration, secretion of proangiogenic molecules (such as HIF-1α, VEGF, SDF-1α), and tube formation of endothelial progenitor cells (EPC) are stimulated by 20-HETE. These effects are mediated through c-Src- and EGFR-mediated downstream signaling pathways, including MAPK and PI3K/Akt pathways, eNOS uncoupling, and NOX/ROS system activation. Therefore, the CYP4A/F-20-HETE system may be a therapeutic target for the treatment of abnormal angiogenic diseases.
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Affiliation(s)
- Li Chen
- Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA
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