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Dai J, Chen H, Fang J, Wu S, Jia Z. Vascular Remodeling: The Multicellular Mechanisms of Pulmonary Hypertension. Int J Mol Sci 2025; 26:4265. [PMID: 40362501 PMCID: PMC12072204 DOI: 10.3390/ijms26094265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2025] [Revised: 04/24/2025] [Accepted: 04/28/2025] [Indexed: 05/15/2025] Open
Abstract
Pulmonary hypertension (PH) is a serious cardiovascular disease caused by a variety of pathogenic factors, which is characterized by increased pulmonary vascular resistance (PVR) and progressive elevation of mean pulmonary artery pressure (mPAP). This disease can lead to right ventricular hypertrophy and, in severe cases, right heart failure and even death. Vascular remodeling-a pathological modification involving aberrant vasoconstriction, cell proliferation, apoptosis resistance, and inflammation in the pulmonary vascular system-is a significant pathological hallmark of PH and a critical process in its progression. Recent studies have found that vascular remodeling involves the participation of a diversity of cellular pathological alterations, such as the dysfunction of pulmonary artery endothelial cells (PAECs), the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs), the phenotypic differentiation of pulmonary artery fibroblasts, the inflammatory response of immune cells, and pericyte proliferation. This review focuses on the mechanisms and the intercellular crosstalk of these cells in the PH process, emphasizing recent advances in knowledge regarding cellular signaling pathways, inflammatory responses, apoptosis, and proliferation. To develop better treatments, a list of possible therapeutic approaches meant to slow down certain biological functions is provided, with the aim of providing new insights into the treatment of PH by simplifying the intricacies of these complex connections. In this review, comprehensive academic databases such as PubMed, Embase, Web of Science, and Google Scholar were systematically searched to discuss studies relevant to human and animal PH, with a focus on vascular remodeling in PH.
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Affiliation(s)
- Jinjin Dai
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming 650500, China; (J.D.); (H.C.); (J.F.)
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Kunming 650500, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Education Department of Yunnan, Kunming 650500, China
| | - Hongyang Chen
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming 650500, China; (J.D.); (H.C.); (J.F.)
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Kunming 650500, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Education Department of Yunnan, Kunming 650500, China
| | - Jindong Fang
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming 650500, China; (J.D.); (H.C.); (J.F.)
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Kunming 650500, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Education Department of Yunnan, Kunming 650500, China
| | - Shiguo Wu
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming 650500, China; (J.D.); (H.C.); (J.F.)
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Kunming 650500, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Education Department of Yunnan, Kunming 650500, China
| | - Zhuangzhuang Jia
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming 650500, China; (J.D.); (H.C.); (J.F.)
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Kunming 650500, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Education Department of Yunnan, Kunming 650500, China
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Fellows AL, Chen CN, Xie C, Iyer N, Schmidt L, Yin X, Yates LA, Mayr M, Cowburn A, Zhao L, Wojciak-Stothard B. ARF6 as a Novel Activator of HIF-2α in Pulmonary Arterial Hypertension. Am J Respir Cell Mol Biol 2025; 72:380-392. [PMID: 39556110 PMCID: PMC12005040 DOI: 10.1165/rcmb.2024-0149oc] [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: 03/28/2024] [Accepted: 11/18/2024] [Indexed: 11/19/2024] Open
Abstract
ARF6 (ADP-ribosylation factor 6), a GTPase associated with cancer metastasis, is activated in the lung endothelium in pulmonary arterial hypertension (PAH). To identify ARF6-regulated pathways relevant to PAH, we performed a state-of-the-art proteomic analysis of human pulmonary artery endothelial cells (HPAECs) overexpressing the wild-type, constitutively active, fast-cycling, and dominant-negative mutants of ARF6. The analysis revealed a novel link of ARF6 with HIF (hypoxia-inducible factor), in addition to endocytotic vesicle trafficking, cell proliferation, angiogenesis, oxidative stress, and lipid metabolism. Active ARF6 markedly increased expression and activity of HIF-2, critical in PAH, with HIF-1 relatively unaffected. Hypoxic ARF6 activation was a prerequisite for HIF-2 activation and HIF-dependent gene expression in HPAECs, PAH blood-derived late-outgrowth endothelial colony-forming cells, and hypoxic mouse lungs in vivo. A novel ARF6 inhibitor, chlortetracycline (CTC), reduced hypoxia-induced HIF-2 activation, proliferation, and angiogenesis in HPAECs and reduced HIF-2 expression in lung and heart tissues of hypoxic mice. PAH endothelial colony-forming cells showed elevated expression and activity of ARF6 and HIF2, which was attenuated by CTC, and oral CTC attenuated development of pulmonary hypertension in chronically hypoxic mice. We identify EGFR (epidermal growth factor receptor) as a direct interactor of ARF6 and EGFR signaling as a crucial mechanism linking ARF6 and HIF activation. In conclusion, we are the first to demonstrate a key role of ARF6 in the regulation of HIF-2α activation in vitro and in vivo and show that HIF-2α, a master regulator of vascular remodeling in PAH, can be targeted by a clinically approved antibiotic CTC.
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Affiliation(s)
| | | | | | | | - Lukas Schmidt
- King’s British Heart Foundation Centre, King’s College London, London, United Kingdom; and
| | | | - Luke A. Yates
- Department of Infectious Disease, Imperial College London, London, United Kingdom
- Francis Crick Institute, London, United Kingdom
| | | | | | - Lan Zhao
- National Heart and Lung Institute and
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Negri S, Reyff Z, Troyano-Rodriguez E, Milan M, Ihuoma J, Tavakol S, Shi H, Patai R, Jiang R, Mohon J, Boma-Iyaye J, Ungvari Z, Csiszar A, Yabluchanskiy A, Moccia F, Tarantini S. Endothelial Colony-Forming Cells (ECFCs) in cerebrovascular aging: Focus on the pathogenesis of Vascular Cognitive Impairment and Dementia (VCID), and treatment prospects. Ageing Res Rev 2025; 104:102672. [PMID: 39884362 DOI: 10.1016/j.arr.2025.102672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 01/21/2025] [Accepted: 01/24/2025] [Indexed: 02/01/2025]
Abstract
Endothelial colony-forming cells (ECFCs), a unique endothelial progenitor subset, are essential for vascular integrity and repair, providing significant regenerative potential. Recent studies highlight their role in cerebrovascular aging, particularly in the pathogenesis of vascular cognitive impairment and dementia (VCID). Aging disrupts ECFC functionality through mechanisms such as oxidative stress, chronic inflammation, and cellular senescence, leading to compromised vascular repair and reduced neurovascular resilience. ECFCs influence key cerebrovascular processes, including neurovascular coupling (NVC), blood-brain barrier (BBB) integrity, and vascular regeneration, which are critical for cognitive health. Age-related decline in ECFC quantity and functionality contributes to vascular rarefaction, diminished cerebral blood flow (CBF), and BBB permeability-processes that collectively exacerbate cognitive decline. This review delves into the multifaceted role of ECFCs in cerebrovascular aging and underscores their potential as therapeutic targets in addressing age-related vascular dysfunctions, presenting new directions for mitigating the effects of aging on brain health.
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Affiliation(s)
- Sharon Negri
- Vascular Cognitive Impairment and Neurodegeneration Program, Dept. of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Zeke Reyff
- Vascular Cognitive Impairment and Neurodegeneration Program, Dept. of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Eva Troyano-Rodriguez
- Vascular Cognitive Impairment and Neurodegeneration Program, Dept. of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Madison Milan
- Vascular Cognitive Impairment and Neurodegeneration Program, Dept. of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Jennifer Ihuoma
- Vascular Cognitive Impairment and Neurodegeneration Program, Dept. of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Sherwin Tavakol
- Vascular Cognitive Impairment and Neurodegeneration Program, Dept. of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Helen Shi
- Vascular Cognitive Impairment and Neurodegeneration Program, Dept. of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Roland Patai
- Vascular Cognitive Impairment and Neurodegeneration Program, Dept. of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Raymond Jiang
- Vascular Cognitive Impairment and Neurodegeneration Program, Dept. of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Casady School, Oklahoma City, OK, USA
| | - Jonah Mohon
- Vascular Cognitive Impairment and Neurodegeneration Program, Dept. of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Oklahoma School of Science and Mathematics, OK, USA
| | - Jed Boma-Iyaye
- Vascular Cognitive Impairment and Neurodegeneration Program, Dept. of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Oklahoma School of Science and Mathematics, OK, USA
| | - Zoltan Ungvari
- Vascular Cognitive Impairment and Neurodegeneration Program, Dept. of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; International Training Program in Geroscience, Doctoral College, Health Sciences Program/Institute of Preventive Medicine and Public Health, Semmelweis University, Budapest, Hungary; Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Anna Csiszar
- Vascular Cognitive Impairment and Neurodegeneration Program, Dept. of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Andriy Yabluchanskiy
- Vascular Cognitive Impairment and Neurodegeneration Program, Dept. of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Francesco Moccia
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso 86100, Italy
| | - Stefano Tarantini
- Vascular Cognitive Impairment and Neurodegeneration Program, Dept. of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; International Training Program in Geroscience, Doctoral College, Health Sciences Program/Institute of Preventive Medicine and Public Health, Semmelweis University, Budapest, Hungary; Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
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Heydari K, Johnson C, Diane Cooper I, Hersi K, Tanba C, Sun J, Solomon MA, Elinoff JM. Flow Cytometric Determination of Circulating Progenitor Cells in Patients With Pulmonary Arterial Hypertension: A Systematic Review. Pulm Circ 2025; 15:e70065. [PMID: 40125448 PMCID: PMC11925724 DOI: 10.1002/pul2.70065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 03/10/2025] [Accepted: 03/12/2025] [Indexed: 03/25/2025] Open
Abstract
Pulmonary arterial hypertension (PAH) is characterized by progressive narrowing and obliteration of distal, pre-capillary pulmonary vessels. Yet, noninvasive biomarkers that reflect this disease-defining process are lacking. A systematic review of PAH studies that measured circulating progenitor cells (CPCs) or circulating endothelial cells (CECs) in PAH by flow cytometry was performed to understand how future studies, leveraging state-of-the-art single-cell analyses, can advance the field. The study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews. Of the 2422 studies identified, 20 met inclusion criteria. Nineteen studies measured CPCs by flow cytometry, only one study examined CECs. A total of 647 PAH patients were included across all 19 CPC studies. Marker schemes chosen to define CPCs, and the methods of flow cytometry used, varied significantly across studies. Meta-analysis of a subgroup of CPC studies (n = 8) similarly identified a significant amount of heterogeneity even amongst studies using the same marker scheme. In conclusion, a systematic review of CPC studies in PAH patients reveals the limitations of the current literature. Future studies should include contemporary risk assessments, disease duration, reporting of comorbid conditions, and serial sampling over time. Furthermore, methods that incorporate best practices for detecting rare cell populations by flow cytometry are essential and should be reported in sufficient detail in future publications. With the emergence of single-cell technologies, future studies of circulating progenitor and endothelial cells in PAH remain relevant and may incorporate several insights from the current review to build upon the existing literature.
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Affiliation(s)
- Kimia Heydari
- Critical Care Medicine DepartmentNIH Clinical Center, National Institutes of HealthBethesdaMarylandUSA
| | - Carrie Johnson
- Critical Care Medicine DepartmentNIH Clinical Center, National Institutes of HealthBethesdaMarylandUSA
| | | | - Kadija Hersi
- National Heart Lung and Blood InstituteNational Institutes of HealthBethesdaMarylandUSA
| | - Carl Tanba
- Department of Pulmonary and Critical Care MedicineTufts Medical CenterBostonMarylandUSA
| | - Junfeng Sun
- Critical Care Medicine DepartmentNIH Clinical Center, National Institutes of HealthBethesdaMarylandUSA
| | - Michael A. Solomon
- Critical Care Medicine DepartmentNIH Clinical Center, National Institutes of HealthBethesdaMarylandUSA
- National Heart Lung and Blood InstituteNational Institutes of HealthBethesdaMarylandUSA
| | - Jason M. Elinoff
- Critical Care Medicine DepartmentNIH Clinical Center, National Institutes of HealthBethesdaMarylandUSA
- National Heart Lung and Blood InstituteNational Institutes of HealthBethesdaMarylandUSA
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Dardi F, Boucly A, Benza R, Frantz R, Mercurio V, Olschewski H, Rådegran G, Rubin LJ, Hoeper MM. Risk stratification and treatment goals in pulmonary arterial hypertension. Eur Respir J 2024; 64:2401323. [PMID: 39209472 PMCID: PMC11525341 DOI: 10.1183/13993003.01323-2024] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 07/09/2024] [Indexed: 09/04/2024]
Abstract
Risk stratification has gained an increasing role in predicting outcomes and guiding the treatment of patients with pulmonary arterial hypertension (PAH). The most predictive prognostic factors are three noninvasive parameters (World Health Organization functional class, 6-min walk distance and natriuretic peptides) that are included in all currently validated risk stratification tools. However, suffering from limitations mainly related to reduced specificity of PAH severity, these variables may not always be adequate in isolation for guiding individualised treatment decisions. Moreover, with effective combination treatment regimens and emerging PAH therapies, markers associated with pulmonary vascular remodelling are expected to become of increasing relevance in guiding the treatment of patients with PAH. While reaching a low mortality risk, assessed with a validated risk tool, remains an important treatment goal, preliminary data suggest that invasive haemodynamics and cardiac imaging may add incremental value in guiding treatment decisions.
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Affiliation(s)
- Fabio Dardi
- Cardiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Athénaïs Boucly
- Université Paris-Saclay, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Raymond Benza
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Robert Frantz
- Department of Cardiovascular Disease, Mayo Clinic, Rochester, MN, USA
| | - Valentina Mercurio
- Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Horst Olschewski
- Div. Pulmonology, Department Internal Medicine, Medical University of Graz, Graz, Austria
| | - Göran Rådegran
- Department of Clinical Sciences Lund, Cardiology, Lund University and The Haemodynamic Lab, VO Heart and Lung Medicine, Skåne University Hospital, Lund, Sweden
| | - Lewis J Rubin
- University of California San Diego School of Medicine, San Diego, CA, USA
| | - Marius M Hoeper
- Department of Respiratory Medicine and Infectious Disease, Hannover Medical School and the German Center for Lung Research (DZL), Hannover, Germany
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Ackermann M, Werlein C, Plucinski E, Leypold S, Kühnel MP, Verleden SE, Khalil HA, Länger F, Welte T, Mentzer SJ, Jonigk DD. The role of vasculature and angiogenesis in respiratory diseases. Angiogenesis 2024; 27:293-310. [PMID: 38580869 PMCID: PMC11303512 DOI: 10.1007/s10456-024-09910-2] [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: 12/20/2023] [Accepted: 02/11/2024] [Indexed: 04/07/2024]
Abstract
In European countries, nearly 10% of all hospital admissions are related to respiratory diseases, mainly chronic life-threatening diseases such as COPD, pulmonary hypertension, IPF or lung cancer. The contribution of blood vessels and angiogenesis to lung regeneration, remodeling and disease progression has been increasingly appreciated. The vascular supply of the lung shows the peculiarity of dual perfusion of the pulmonary circulation (vasa publica), which maintains a functional blood-gas barrier, and the bronchial circulation (vasa privata), which reveals a profiled capacity for angiogenesis (namely intussusceptive and sprouting angiogenesis) and alveolar-vascular remodeling by the recruitment of endothelial precursor cells. The aim of this review is to outline the importance of vascular remodeling and angiogenesis in a variety of non-neoplastic and neoplastic acute and chronic respiratory diseases such as lung infection, COPD, lung fibrosis, pulmonary hypertension and lung cancer.
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Affiliation(s)
- Maximilian Ackermann
- Institute of Pathology, University Clinics of RWTH University, Aachen, Germany.
- Institute of Pathology and Molecular Pathology, Helios University Clinic Wuppertal, University of Witten/Herdecke, Witten, Germany.
- Institute of Anatomy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
| | | | - Edith Plucinski
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Sophie Leypold
- Institute of Pathology, University Clinics of RWTH University, Aachen, Germany
| | - Mark P Kühnel
- Institute of Pathology, University Clinics of RWTH University, Aachen, Germany
- Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany
| | - Stijn E Verleden
- Antwerp Surgical Training, Anatomy and Research Centre (ASTARC), University of Antwerp, Antwerp, Belgium
| | - Hassan A Khalil
- Division of Thoracic and Cardiac Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, USA
- Laboratory of Adaptive and Regenerative Biology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Florian Länger
- Institute of Pathology, University Clinics of RWTH University, Aachen, Germany
| | - Tobias Welte
- Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany
- Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
| | - Steven J Mentzer
- Division of Thoracic and Cardiac Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, USA
- Laboratory of Adaptive and Regenerative Biology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Danny D Jonigk
- Institute of Pathology, University Clinics of RWTH University, Aachen, Germany
- Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany
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Frantz RP, McLaughlin VV, Sahay S, Escribano Subías P, Zolty RL, Benza RL, Channick RN, Chin KM, Hemnes AR, Howard LS, Sitbon O, Vachiéry JL, Zamanian RT, Cravets M, Roscigno RF, Mottola D, Osterhout R, Bruey JM, Elman E, Tompkins CA, Parsley E, Aranda R, Zisman LS, Ghofrani HA. Seralutinib in adults with pulmonary arterial hypertension (TORREY): a randomised, double-blind, placebo-controlled phase 2 trial. THE LANCET. RESPIRATORY MEDICINE 2024; 12:523-534. [PMID: 38705167 DOI: 10.1016/s2213-2600(24)00072-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 02/20/2024] [Accepted: 02/23/2024] [Indexed: 05/07/2024]
Abstract
BACKGROUND Morbidity and mortality in pulmonary arterial hypertension (PAH) remain high. Activation of platelet-derived growth factor receptor, colony stimulating factor 1 receptor, and mast or stem cell growth factor receptor kinases stimulates inflammatory, proliferative, and fibrotic pathways driving pulmonary vascular remodelling in PAH. Seralutinib, an inhaled kinase inhibitor, targets these pathways. We aimed to evaluate the efficacy and safety of seralutinib in patients with PAH receiving standard background therapy. METHODS The TORREY trial was a phase 2, randomised, multicentre, multinational, double-blind, placebo-controlled study. Patients with PAH from 40 hospital and community sites were randomly assigned 1:1 via interactive response technologies to receive seralutinib (60 mg twice daily for 2 weeks, then increased to 90 mg twice daily as tolerated) or placebo by dry powder inhaler twice daily for 24 weeks. Randomisation was stratified by baseline pulmonary vascular resistance (PVR; <800 dyne·s/cm5 and ≥800 dyne·s/cm5). Patients were eligible if classified as WHO Group 1 PH (PAH), WHO Functional Class II or III, with a PVR of 400 dyne·s/cm5 or more, and a 6 min walk distance of between 150 m and 550 m. The primary endpoint was change in PVR from baseline to 24 weeks. Analyses for efficacy endpoints were conducted in randomly assigned patients (intention-to-treat population). Safety analyses included all patients who received the study drug. TORREY was registered with ClinicalTrials.gov (NCT04456998) and EudraCT (2019-002669-37) and is completed. FINDINGS From Nov 12, 2020, to April 20, 2022, 151 patients were screened for eligibility, and following exclusions, 86 adults receiving PAH background therapy were randomly assigned to seralutinib (n=44; four male, 40 female) or placebo (n=42; four male, 38 female), and comprised the intention-to-treat population. At baseline, treatment groups were balanced except for a higher representation of WHO Functional Class II patients in the seralutinib group. The least squares mean change from baseline to week 24 in PVR was 21·2 dyne·s/cm5 (95% CI -37·4 to 79·8) for the placebo group and -74·9 dyne·s/cm5 (-139·7 to -10·2) for the seralutinib group. The least squares mean difference between the seralutinib and placebo groups for change in PVR was -96·1 dyne·s/cm5 (95% CI -183·5 to -8·8; p=0·03). The most common treatment-emergent adverse event in both treatment groups was cough: 16 (38%) of 42 patients in the placebo group; 19 (43%) of 44 patients in the seralutinib group. INTERPRETATION Treatment with inhaled seralutinib significantly decreased PVR, meeting the primary endpoint of the study among patients receiving background therapy for PAH. FUNDING Gossamer Bio.
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Affiliation(s)
- Robert P Frantz
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
| | - Vallerie V McLaughlin
- Department of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA; Frankel Cardiovascular Center, Ann Arbor, MI, USA
| | - Sandeep Sahay
- Division of Pulmonary, Critical Care & Sleep Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Pilar Escribano Subías
- Department of Cardiology, CIBERCV, Complutense University, Madrid, Spain; University Hospital 12 de Octubre, Madrid, Spain
| | - Ronald L Zolty
- Department of Cardiovascular Medicine, University of Nebraska College of Medicine, Omaha, NE, USA; University of Nebraska Medical Center, Omaha, NE, USA
| | - Raymond L Benza
- Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Mount Sinai Hospital, New York, NY, USA
| | - Richard N Channick
- Department of Clinical Medicine, University of California Los Angeles, Los Angeles, CA, USA; UCLA Medical Center, Los Angeles, CA, USA
| | - Kelly M Chin
- Division of Pulmonary and Critical Care Medicine, UT Southwestern Medical Center, Dallas, TX, USA; UT Southwestern Medical Center, Dallas, TX, USA
| | - Anna R Hemnes
- Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN, USA; Vanderbilt University Medical Center, Nashville, TN, USA
| | - Luke S Howard
- National Pulmonary Hypertension Service, Imperial College Healthcare NHS Trust, London, UK; Hammersmith Hospital, London, UK
| | - Olivier Sitbon
- Department of Respiratory Medicine, Hôpital Bicêtre (AP-HP), Le Kremlin-Bicêtre, France; Université Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Jean-Luc Vachiéry
- Department of Cardiology, Université Libre de Bruxelles, Brussels, Belgium; HUB-Hôpital Erasme, Brussels, Belgium
| | - Roham T Zamanian
- Department of Medicine-Pulmonary, Allergy & Critical Care Medicine, Stanford University School of Medicine, Stanford, CA, USA; Stanford Medicine, Stanford, CA, USA
| | | | | | | | | | | | | | | | | | | | | | - Hossein-Ardeschir Ghofrani
- Department of Internal Medicine, Justus-Liebig-University Giessen and Marburg Lung Center (UGMLC), Giessen, Germany; Institute for Lung Health, Cardio-Pulmonary Institute, Giessen, Germany; German Center for Lung Research (DZL), Giessen, Germany; Department of Medicine, Imperial College, London, UK
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8
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Imai R, Adachi S, Yoshida M, Shimokata S, Nakano Y, Okumura N, Murohara T, Kondo T. Clinical usefulness of endothelial progenitor cells in predicting the efficacy of riociguat in chronic thromboembolic pulmonary hypertension. NAGOYA JOURNAL OF MEDICAL SCIENCE 2024; 86:292-303. [PMID: 38962405 PMCID: PMC11219221 DOI: 10.18999/nagjms.86.2.292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 10/11/2023] [Indexed: 07/05/2024]
Abstract
Endothelial dysfunction is important in the pathology of pulmonary hypertension, and circulating endothelial progenitor cells (EPCs) have been studied to evaluate endothelial dysfunction. In patients with chronic thromboembolic pulmonary hypertension (CTEPH), riociguat reportedly increases the number of circulating EPCs. However, the relationship between EPC numbers at baseline and changes in clinical parameters after riociguat administration has not been fully elucidated. Here, we evaluated 27 treatment-naïve patients with CTEPH and analyzed the relationships between EPC number at diagnosis and clinical variables (age, hemodynamics, atrial blood gas parameters, brain natriuretic peptide, and exercise tolerance) before and after riociguat initiation. EPCs were defined as CD45dim CD34+ CD133+ cells and measured by flow cytometry. A low number of circulating EPCs at diagnosis was significantly correlated with increased reductions in mean pulmonary arterial pressure (mPAP) (correlation coefficient = 0.535, P = 0.004) and right atrial pressure (correlation coefficient = 0.618, P = 0.001) upon riociguat treatment. We then divided the study population into two groups according to the mPAP change: a weak-response group (a decrease in mPAP of 4 mmHg or less) and a strong-response group (a decrease in mPAP of more than 4 mmHg). The number of EPCs at diagnosis was significantly lower in the strong-response group than in the weak-response group (P = 0.022), but there were no significant differences in other clinical variables or in medication profiles. In conclusion, circulating EPC numbers could be a potential predictor of the therapeutic effect of riociguat in CTEPH patients.
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Affiliation(s)
- Ryo Imai
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Cardiology, NHO Nagoya Medical Center, Nagoya, Japan
| | - Shiro Adachi
- Department of Cardiology, Nagoya University Hospital, Nagoya, Japan
| | - Masahiro Yoshida
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shigetake Shimokata
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshihisa Nakano
- Department of Cardiology, Nagoya University Hospital, Nagoya, Japan
| | - Naoki Okumura
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Toyoaki Murohara
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takahisa Kondo
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Cardiology, NHO Nagoya Medical Center, Nagoya, Japan
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9
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Ye L, Liu R, Li Q, Zhou C, Tan X. Dysregulated VEGF/VEGFR-2 Signaling and Plexogenic Lesions in the Embryonic Lungs of Chickens Predisposed to Pulmonary Arterial Hypertension. Int J Mol Sci 2024; 25:4489. [PMID: 38674074 PMCID: PMC11049811 DOI: 10.3390/ijms25084489] [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: 12/13/2023] [Revised: 04/03/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
Plexiform lesions are a hallmark of pulmonary arterial hypertension (PAH) in humans and are proposed to stem from dysfunctional angioblasts. Broiler chickens (Gallus gallus) are highly susceptible to PAH, with plexiform-like lesions observed in newly hatched individuals. Here, we reported the emergence of plexiform-like lesions in the embryonic lungs of broiler chickens. Lung samples were collected from broiler chickens at embryonic day 20 (E20), hatch, and one-day-old, with PAH-resistant layer chickens as controls. Plexiform lesions consisting of CD133+/vascular endothelial growth factor receptor type-2 (VEGFR-2)+ angioblasts were exclusively observed in broiler embryos and sporadically in layer embryos. Distinct gene profiles of angiogenic factors were observed between the two strains, with impaired VEGF-A/VEGFR-2 signaling correlating with lesion development and reduced arteriogenesis. Pharmaceutical inhibition of VEGFR-2 resulted in enhanced lesion development in layer embryos. Moreover, broiler embryonic lungs displayed increased activation of HIF-1α and nuclear factor erythroid 2-related factor 2 (Nrf2), indicating a hypoxic state. Remarkably, we found a negative correlation between lung Nrf2 activation and VEGF-A and VEGFR-2 expression. In vitro studies indicated that Nrf2 overactivation restricted VEGF signaling in endothelial progenitor cells. The findings from broiler embryos suggest an association between plexiform lesion development and impaired VEGF system due to aberrant activation of Nrf2.
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Affiliation(s)
- Lujie Ye
- Department of Veterinary Medicine, Zhejiang University, Hangzhou 310058, China
- Center for Veterinary Sciences, Zhejiang University, Hangzhou 310058, China
| | - Rui Liu
- Department of Veterinary Medicine, Zhejiang University, Hangzhou 310058, China
- Center for Veterinary Sciences, Zhejiang University, Hangzhou 310058, China
| | - Qinghao Li
- Department of Veterinary Medicine, Zhejiang University, Hangzhou 310058, China
- Center for Veterinary Sciences, Zhejiang University, Hangzhou 310058, China
| | - Chunzhen Zhou
- Department of Veterinary Medicine, Zhejiang University, Hangzhou 310058, China
- Center for Veterinary Sciences, Zhejiang University, Hangzhou 310058, China
| | - Xun Tan
- Department of Veterinary Medicine, Zhejiang University, Hangzhou 310058, China
- Center for Veterinary Sciences, Zhejiang University, Hangzhou 310058, China
- Institute of Preventive Veterinary Sciences, Zhejiang University, Hangzhou 310058, China
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10
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Singh N, Al-Naamani N, Brown MB, Long GM, Thenappan T, Umar S, Ventetuolo CE, Lahm T. Extrapulmonary manifestations of pulmonary arterial hypertension. Expert Rev Respir Med 2024; 18:189-205. [PMID: 38801029 PMCID: PMC11713041 DOI: 10.1080/17476348.2024.2361037] [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: 12/05/2023] [Accepted: 05/24/2024] [Indexed: 05/29/2024]
Abstract
INTRODUCTION Extrapulmonary manifestations of pulmonary arterial hypertension (PAH) may play a critical pathobiological role and a deeper understanding will advance insight into mechanisms and novel therapeutic targets. This manuscript reviews our understanding of extrapulmonary manifestations of PAH. AREAS COVERED A group of experts was assembled and a complimentary PubMed search performed (October 2023 - March 2024). Inflammation is observed throughout the central nervous system and attempts at manipulation are an encouraging step toward novel therapeutics. Retinal vascular imaging holds promise as a noninvasive method of detecting early disease and monitoring treatment responses. PAH patients have gut flora alterations and dysbiosis likely plays a role in systemic inflammation. Despite inconsistent observations, the roles of obesity, insulin resistance and dysregulated metabolism may be illuminated by deep phenotyping of body composition. Skeletal muscle dysfunction is perpetuated by metabolic dysfunction, inflammation, and hypoperfusion, but exercise training shows benefit. Renal, hepatic, and bone marrow abnormalities are observed in PAH and may represent both end-organ damage and disease modifiers. EXPERT OPINION Insights into systemic manifestations of PAH will illuminate disease mechanisms and novel therapeutic targets. Additional study is needed to understand whether extrapulmonary manifestations are a cause or effect of PAH and how manipulation may affect outcomes.
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Affiliation(s)
- Navneet Singh
- Department of Medicine, Warren Alpert School of Medicine at Brown University, Providence, RI
| | - Nadine Al-Naamani
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Mary Beth Brown
- Department of Rehabilitation Medicine, University of Washington School of Medicine, Seattle, WA
| | - Gary Marshall Long
- Department of Kinesiology, Health and Sport Sciences, University of Indianapolis, Indianapolis, IN
| | - Thenappan Thenappan
- Section of Advanced Heart Failure and Pulmonary Hypertension, Cardiovascular Division, University of Minnesota, Minneapolis, MN
| | - Soban Umar
- Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Corey E. Ventetuolo
- Department of Medicine, Warren Alpert School of Medicine at Brown University, Providence, RI
- Department of Health Services, Policy and Practice, Brown University, Providence, RI
| | - Tim Lahm
- Department of Medicine, National Jewish Health, Denver, CO
- Department of Medicine, University of Colorado, Aurora, CO
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO
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11
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Whitworth CP, Polacheck WJ. Vascular organs-on-chip made with patient-derived endothelial cells: technologies to transform drug discovery and disease modeling. Expert Opin Drug Discov 2024; 19:339-351. [PMID: 38117223 PMCID: PMC10922379 DOI: 10.1080/17460441.2023.2294947] [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: 06/30/2023] [Accepted: 12/11/2023] [Indexed: 12/21/2023]
Abstract
INTRODUCTION Vascular diseases impart a tremendous burden on healthcare systems in the United States and across the world. Efforts to improve therapeutic interventions are hindered by limitations of current experimental models. The integration of patient-derived cells with organ-on-chip (OoC) technology is a promising avenue for preclinical drug screening that improves upon traditional cell culture and animal models. AREAS COVERED The authors review induced pluripotent stem cells (iPSC) and blood outgrowth endothelial cells (BOEC) as two sources for patient-derived endothelial cells (EC). They summarize several studies that leverage patient-derived EC and OoC for precision disease modeling of the vasculature, with a focus on applications for drug discovery. They also highlight the utility of patient-derived EC in other translational endeavors, including ex vivo organogenesis and multi-organ-chip integration. EXPERT OPINION Precision disease modeling continues to mature in the academic space, but end-use by pharmaceutical companies is currently limited. To fully realize their transformative potential, OoC systems must balance their complexity with their ability to integrate with the highly standardized and high-throughput experimentation required for drug discovery and development.
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Affiliation(s)
- Chloe P Whitworth
- Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - William J Polacheck
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
- McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Joint Department of Biomedical Engineering, North Carolina State University, Raleigh, NC, USA
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12
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Piper B, Bogamuwa S, Hossain T, Farkas D, Rosas L, Green AC, Newcomb G, Sun N, Ovando-Ricardez JA, Horowitz JC, Bhagwani AR, Yang H, Kudryashova TV, Rojas M, Mora AL, Yan P, Mallampalli RK, Goncharova EA, Eckmann DM, Farkas L. RAB7 deficiency impairs pulmonary artery endothelial function and promotes pulmonary hypertension. J Clin Invest 2024; 134:e169441. [PMID: 38015641 PMCID: PMC10836802 DOI: 10.1172/jci169441] [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: 02/07/2023] [Accepted: 11/21/2023] [Indexed: 11/30/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is a devastating and progressive disease with limited treatment options. Endothelial dysfunction plays a central role in the development and progression of PAH, yet the underlying mechanisms are incompletely understood. The endosome-lysosome system is important to maintain cellular health, and the small GTPase RAB7 regulates many functions of this system. Here, we explored the role of RAB7 in endothelial cell (EC) function and lung vascular homeostasis. We found reduced expression of RAB7 in ECs from patients with PAH. Endothelial haploinsufficiency of RAB7 caused spontaneous pulmonary hypertension (PH) in mice. Silencing of RAB7 in ECs induced broad changes in gene expression revealed via RNA-Seq, and RAB7-silenced ECs showed impaired angiogenesis and expansion of a senescent cell fraction, combined with impaired endolysosomal trafficking and degradation, suggesting inhibition of autophagy at the predegradation level. Furthermore, mitochondrial membrane potential and oxidative phosphorylation were decreased, and glycolysis was enhanced. Treatment with the RAB7 activator ML-098 reduced established PH in rats with chronic hypoxia/SU5416. In conclusion, we demonstrate for the first time to our knowledge the fundamental impairment of EC function by loss of RAB7, causing PH, and show RAB7 activation to be a potential therapeutic strategy in a preclinical model of PH.
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Affiliation(s)
- Bryce Piper
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine
- Davis Heart and Lung Research Institute
| | - Srimathi Bogamuwa
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine
- Davis Heart and Lung Research Institute
| | | | - Daniela Farkas
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine
- Davis Heart and Lung Research Institute
| | - Lorena Rosas
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine
- Davis Heart and Lung Research Institute
| | | | - Geoffrey Newcomb
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine
- Davis Heart and Lung Research Institute
| | - Nuo Sun
- Davis Heart and Lung Research Institute
- Department of Cell Biology and Physiology, The Ohio State University (OSU), Columbus, Ohio, USA
| | - Jose A. Ovando-Ricardez
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine
- Davis Heart and Lung Research Institute
| | - Jeffrey C. Horowitz
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine
- Davis Heart and Lung Research Institute
| | - Aneel R. Bhagwani
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine
- Davis Heart and Lung Research Institute
- Department of Physiology, Ziauddin University, Karachi, Pakistan
| | - Hu Yang
- Linda and Bipin Doshi Department of Chemical and Biochemical Engineering, Missouri University of Science and Technology, Rolla, Missouri, USA
| | - Tatiana V. Kudryashova
- University of Pittsburgh, Heart, Blood, and Vascular Medicine Institute, Pittsburgh, Pennsylvania, USA
| | - Mauricio Rojas
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine
- Davis Heart and Lung Research Institute
| | - Ana L. Mora
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine
- Davis Heart and Lung Research Institute
| | - Pearlly Yan
- Division of Hematology, Department of Internal Medicine and The James Cancer Center, OSU, Columbus, Ohio, USA
| | - Rama K. Mallampalli
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine
- Davis Heart and Lung Research Institute
| | - Elena A. Goncharova
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of California Davis, Davis, California, USA
| | - David M. Eckmann
- Department of Anesthesiology, and
- Center for Medical and Engineering Innovation, OSU, Columbus, Ohio, USA
| | - Laszlo Farkas
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine
- Davis Heart and Lung Research Institute
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13
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Lin A, Brittan M, Baker AH, Dimmeler S, Fisher EA, Sluimer JC, Misra A. Clonal Expansion in Cardiovascular Pathology. JACC Basic Transl Sci 2024; 9:120-144. [PMID: 38362345 PMCID: PMC10864919 DOI: 10.1016/j.jacbts.2023.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 04/13/2023] [Accepted: 04/14/2023] [Indexed: 02/17/2024]
Abstract
Clonal expansion refers to the proliferation and selection of advantageous "clones" that are better suited for survival in a Darwinian manner. In recent years, we have greatly enhanced our understanding of cell clonality in the cardiovascular context. However, our knowledge of the underlying mechanisms behind this clonal selection is still severely limited. There is a transpiring pattern of clonal expansion of smooth muscle cells and endothelial cells-and, in some cases, macrophages-in numerous cardiovascular diseases irrespective of their differing microenvironments. These findings indirectly suggest the possible existence of stem-like vascular cells which are primed to respond during disease. Subsequent clones may undergo further phenotypic changes to adopt either protective or detrimental roles. By investigating these clone-forming vascular cells, we may be able to harness this inherent clonal nature for future therapeutic intervention. This review comprehensively discusses what is currently known about clonal expansion across the cardiovascular field. Comparisons of the clonal nature of vascular cells in atherosclerosis (including clonal hematopoiesis of indeterminate potential), pulmonary hypertension, aneurysm, blood vessel injury, ischemia- and tumor-induced angiogenesis, and cerebral cavernous malformations are evaluated. Finally, we discuss the potential clinical implications of these findings and propose that proper understanding and specific targeting of these clonal cells may provide unique therapeutic options for the treatment of these cardiovascular conditions.
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Affiliation(s)
- Alexander Lin
- Atherosclerosis and Vascular Remodeling Group, Heart Research Institute, Sydney, New South Wales, Australia
- School of Biomedical Engineering, Faculty of Engineering, The University of Sydney, Sydney, New South Wales, Australia
| | - Mairi Brittan
- Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Andrew H. Baker
- Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
- CARIM School for Cardiovascular Sciences, Department of Pathology, Maastricht University Medical Center (MUMC), Maastricht, the Netherlands
| | - Stefanie Dimmeler
- Institute for Cardiovascular Regeneration, Goethe University Frankfurt, Frankfurt, Germany
- German Center for Cardiovascular Research (DZHK), partner site Frankfurt Rhine-Main, Berlin, Germany
- Cardiopulmonary Institute, Goethe University Frankfurt, Frankfurt, Germany
| | - Edward A. Fisher
- Department of Medicine/Division of Cardiology, New York University Grossman School of Medicine, New York, New York, USA
- Cardiovascular Research Center, New York University Grossman School of Medicine, New York, New York, USA
| | - Judith C. Sluimer
- Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
- CARIM School for Cardiovascular Sciences, Department of Pathology, Maastricht University Medical Center (MUMC), Maastricht, the Netherlands
| | - Ashish Misra
- Atherosclerosis and Vascular Remodeling Group, Heart Research Institute, Sydney, New South Wales, Australia
- Heart Research Institute, The University of Sydney, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
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14
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Simmons Beck R, Liang OD, Klinger JR. Light at the ENDothelium-role of Sox17 and Runx1 in endothelial dysfunction and pulmonary arterial hypertension. Front Cardiovasc Med 2023; 10:1274033. [PMID: 38028440 PMCID: PMC10656768 DOI: 10.3389/fcvm.2023.1274033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 10/11/2023] [Indexed: 12/01/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is a progressive disease that is characterized by an obliterative vasculopathy of the distal pulmonary circulation. Despite significant progress in our understanding of the pathophysiology, currently approved medical therapies for PAH act primarily as pulmonary vasodilators and fail to address the underlying processes that lead to the development and progression of the disease. Endothelial dysregulation in response to stress, injury or physiologic stimuli followed by perivascular infiltration of immune cells plays a prominent role in the pulmonary vascular remodeling of PAH. Over the last few decades, our understanding of endothelial cell dysregulation has evolved and brought to light a number of transcription factors that play important roles in vascular homeostasis and angiogenesis. In this review, we examine two such factors, SOX17 and one of its downstream targets, RUNX1 and the emerging data that implicate their roles in the pathogenesis of PAH. We review their discovery and discuss their function in angiogenesis and lung vascular development including their roles in endothelial to hematopoietic transition (EHT) and their ability to drive progenitor stem cells toward an endothelial or myeloid fate. We also summarize the data from studies that link mutations in Sox17 with an increased risk of developing PAH and studies that implicate Sox17 and Runx1 in the pathogenesis of PAH. Finally, we review the results of recent studies from our lab demonstrating the efficacy of preventing and reversing pulmonary hypertension in animal models of PAH by deleting RUNX1 expression in endothelial or myeloid cells or by the use of RUNX1 inhibitors. By investigating PAH through the lens of SOX17 and RUNX1 we hope to shed light on the role of these transcription factors in vascular homeostasis and endothelial dysregulation, their contribution to pulmonary vascular remodeling in PAH, and their potential as novel therapeutic targets for treating this devastating disease.
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Affiliation(s)
- Robert Simmons Beck
- Division of Pulmonary, Sleep and Critical Care Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, United States
| | - Olin D. Liang
- Division of Hematology/Oncology, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, United States
| | - James R. Klinger
- Division of Pulmonary, Sleep and Critical Care Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, United States
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15
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Zheng R, Xu T, Wang X, Yang L, Wang J, Huang X. Stem cell therapy in pulmonary hypertension: current practice and future opportunities. Eur Respir Rev 2023; 32:230112. [PMID: 37758272 PMCID: PMC10523152 DOI: 10.1183/16000617.0112-2023] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 07/13/2023] [Indexed: 09/30/2023] Open
Abstract
Pulmonary hypertension (PH) is a progressive disease characterised by elevated pulmonary arterial pressure and right-sided heart failure. While conventional drug therapies, including prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors, have been shown to improve the haemodynamic abnormalities of patients with PH, the 5-year mortality rate remains high. Thus, novel therapies are urgently required to prolong the survival of patients with PH. Stem cell therapies, including mesenchymal stem cells, endothelial progenitor cells and induced pluripotent stem cells, have shown therapeutic potential for the treatment of PH and clinical trials on stem cell therapies for PH are ongoing. This review aims to present the latest preclinical achievements of stem cell therapies, focusing on the therapeutic effects of clinical trials and discussing the challenges and future perspectives of large-scale applications.
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Affiliation(s)
- Ruixuan Zheng
- Division of Pulmonary Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, China
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- These authors contributed equally to this work
| | - Tingting Xu
- Division of Pulmonary Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, China
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- These authors contributed equally to this work
| | - Xinghong Wang
- Division of Pulmonary Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, China
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lehe Yang
- Division of Pulmonary Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, China
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jian Wang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Xiaoying Huang
- Division of Pulmonary Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, China
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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16
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Pullamsetti SS, Sitapara R, Osterhout R, Weiss A, Carter LL, Zisman LS, Schermuly RT. Pharmacology and Rationale for Seralutinib in the Treatment of Pulmonary Arterial Hypertension. Int J Mol Sci 2023; 24:12653. [PMID: 37628831 PMCID: PMC10454154 DOI: 10.3390/ijms241612653] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/25/2023] [Accepted: 07/31/2023] [Indexed: 08/27/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is a complex disorder characterized by vascular remodeling and a consequent increase in pulmonary vascular resistance. The histologic hallmarks of PAH include plexiform and neointimal lesions of the pulmonary arterioles, which are composed of dysregulated, apoptosis-resistant endothelial cells and myofibroblasts. Platelet-derived growth factor receptors (PDGFR) α and β, colony stimulating factor 1 receptor (CSF1R), and mast/stem cell growth factor receptor kit (c-KIT) are closely related kinases that have been implicated in PAH progression. In addition, emerging data indicate significant crosstalk between PDGF signaling and the bone morphogenetic protein receptor type 2 (BMPR2)/transforming growth factor β (TGFβ) receptor axis. This review will discuss the importance of the PDGFR-CSF1R-c-KIT signaling network in PAH pathogenesis, present evidence that the inhibition of all three nodes in this kinase network is a potential therapeutic approach for PAH, and highlight the therapeutic potential of seralutinib, currently in development for PAH, which targets these pathways.
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Affiliation(s)
- Soni Savai Pullamsetti
- Lung Vascular Epigenetics, Center for Infection and Genomics of the Lung (CIGL), Justus-Liebig-Universität Gießen, Aulweg 132, 35392 Giessen, Germany;
| | | | | | - Astrid Weiss
- UGMLC Pulmonale Pharmakotherapie, Biomedizinisches Forschungszentrum Seltersberg (BFS), Justus-Liebig-Universität Gießen, Schubertstraße 81, 35392 Giessen, Germany;
| | | | | | - Ralph Theo Schermuly
- Department of Internal Medicine, Justus-Liebig-University Giessen, Aulweg 130, 35392 Giessen, Germany
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17
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Hong J, Wong B, Huynh C, Tang B, Ruffenach G, Li M, Umar S, Yang X, Eghbali M. Tm4sf1-marked Endothelial Subpopulation Is Dysregulated in Pulmonary Arterial Hypertension. Am J Respir Cell Mol Biol 2023; 68:381-394. [PMID: 36252184 PMCID: PMC10112423 DOI: 10.1165/rcmb.2022-0020oc] [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: 01/11/2022] [Accepted: 10/17/2022] [Indexed: 11/24/2022] Open
Abstract
The identification and role of endothelial progenitor cells in pulmonary arterial hypertension (PAH) remain controversial. Single-cell omics analysis can shed light on endothelial progenitor cells and their potential contribution to PAH pathobiology. We aim to identify endothelial cells that may have stem/progenitor potential in rat lungs and assess their relevance to PAH. Differential expression, gene set enrichment, cell-cell communication, and trajectory reconstruction analyses were performed on lung endothelial cells from single-cell RNA sequencing of Sugen-hypoxia, monocrotaline, and control rats. Relevance to human PAH was assessed in multiple independent blood and lung transcriptomic data sets. Rat lung endothelial cells were visualized by immunofluorescence in situ, analyzed by flow cytometry, and assessed for tubulogenesis in vitro. A subpopulation of endothelial cells (endothelial arterial type 2 [EA2]) marked by Tm4sf1 (transmembrane 4 L six family member 1), a gene strongly implicated in cancer, harbored a distinct transcriptomic signature enriched for angiogenesis and CXCL12 signaling. Trajectory analysis predicted that EA2 has a less differentiated state compared with other endothelial subpopulations. Analysis of independent data sets revealed that TM4SF1 is downregulated in lungs and endothelial cells from patients and PAH models, is a marker for hematopoietic stem cells, and is upregulated in PAH circulation. TM4SF1+CD31+ rat lung endothelial cells were visualized in distal pulmonary arteries, expressed hematopoietic marker CD45, and formed tubules in coculture with lung fibroblasts. Our study uncovered a novel Tm4sf1-marked subpopulation of rat lung endothelial cells that may have stem/progenitor potential and demonstrated its relevance to PAH. Future studies are warranted to further elucidate the role of EA2 and Tm4sf1 in PAH.
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Affiliation(s)
- Jason Hong
- Division of Pulmonary and Critical Care Medicine
| | - Brenda Wong
- Division of Pulmonary and Critical Care Medicine
| | | | - Brian Tang
- Department of Integrative Biology and Physiology, and
| | - Gregoire Ruffenach
- Department of Anesthesiology and Perioperative Medicine, University of California, Los Angeles, Los Angeles, California
| | - Min Li
- Department of Anesthesiology and Perioperative Medicine, University of California, Los Angeles, Los Angeles, California
| | - Soban Umar
- Department of Anesthesiology and Perioperative Medicine, University of California, Los Angeles, Los Angeles, California
| | - Xia Yang
- Department of Integrative Biology and Physiology, and
| | - Mansoureh Eghbali
- Department of Anesthesiology and Perioperative Medicine, University of California, Los Angeles, Los Angeles, California
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18
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Piper B, Bogamuwa S, Hossain T, Farkas D, Rosas L, Green A, Newcomb G, Sun N, Horowitz JC, Bhagwani AR, Yang H, Kudryashova TV, Rojas M, Mora AL, Yan P, Mallampalli RK, Goncharova EA, Eckmann DM, Farkas L. RAB7 deficiency impairs pulmonary artery endothelial function and promotes pulmonary hypertension. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.03.526842. [PMID: 36778418 PMCID: PMC9915659 DOI: 10.1101/2023.02.03.526842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Pulmonary arterial hypertension (PAH) is a devastating and progressive disease with limited treatment options. Endothelial dysfunction plays a central role in development and progression of PAH, yet the underlying mechanisms are incompletely understood. The endosome-lysosome system is important to maintain cellular health and the small GTPase RAB7 regulates many functions of this system. Here, we explored the role of RAB7 in endothelial cell (EC) function and lung vascular homeostasis. We found reduced expression of RAB7 in ECs from PAH patients. Endothelial haploinsufficiency of RAB7 caused spontaneous PH in mice. Silencing of RAB7 in ECs induced broad changes in gene expression revealed via RNA sequencing and RAB7 silenced ECs showed impaired angiogenesis, expansion of a senescent cell fraction, combined with impaired endolysosomal trafficking and degradation, which suggests inhibition of autophagy at the pre-degradation level. Further, mitochondrial membrane potential and oxidative phosphorylation were decreased, and glycolysis was enhanced. Treatment with the RAB7 activator ML-098 reduced established PH in chronic hypoxia/SU5416 rats. In conclusion, we demonstrate here for the first time the fundamental impairment of EC function by loss of RAB7 that leads to PH and show RAB7 activation as a potential therapeutic strategy in a preclinical model of PH.
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Bousseau S, Sobrano Fais R, Gu S, Frump A, Lahm T. Pathophysiology and new advances in pulmonary hypertension. BMJ MEDICINE 2023; 2:e000137. [PMID: 37051026 PMCID: PMC10083754 DOI: 10.1136/bmjmed-2022-000137] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 02/02/2023] [Indexed: 04/14/2023]
Abstract
Pulmonary hypertension is a progressive and often fatal cardiopulmonary condition characterised by increased pulmonary arterial pressure, structural changes in the pulmonary circulation, and the formation of vaso-occlusive lesions. These changes lead to increased right ventricular afterload, which often progresses to maladaptive right ventricular remodelling and eventually death. Pulmonary arterial hypertension represents one of the most severe and best studied types of pulmonary hypertension and is consistently targeted by drug treatments. The underlying molecular pathogenesis of pulmonary hypertension is a complex and multifactorial process, but can be characterised by several hallmarks: inflammation, impaired angiogenesis, metabolic alterations, genetic or epigenetic abnormalities, influence of sex and sex hormones, and abnormalities in the right ventricle. Current treatments for pulmonary arterial hypertension and some other types of pulmonary hypertension target pathways involved in the control of pulmonary vascular tone and proliferation; however, these treatments have limited efficacy on patient outcomes. This review describes key features of pulmonary hypertension, discusses current and emerging therapeutic interventions, and points to future directions for research and patient care. Because most progress in the specialty has been made in pulmonary arterial hypertension, this review focuses on this type of pulmonary hypertension. The review highlights key pathophysiological concepts and emerging therapeutic directions, targeting inflammation, cellular metabolism, genetics and epigenetics, sex hormone signalling, bone morphogenetic protein signalling, and inhibition of tyrosine kinase receptors.
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Affiliation(s)
- Simon Bousseau
- Division of Pulmonary, Sleep, and Critical Care Medicine, National Jewish Health, Denver, CO, USA
| | - Rafael Sobrano Fais
- Division of Pulmonary, Sleep, and Critical Care Medicine, National Jewish Health, Denver, CO, USA
| | - Sue Gu
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Cardiovascular Pulmonary Research Lab, University of Colorado School of Medicine, Aurora, CO, USA
| | - Andrea Frump
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Tim Lahm
- Division of Pulmonary, Sleep, and Critical Care Medicine, National Jewish Health, Denver, CO, USA
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Rocky Mountain Regional Veteran Affairs Medical Center, Aurora, CO, USA
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20
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Alzaydi MM, Abdul-Salam VB, Whitwell HJ, Russomanno G, Glynos A, Capece D, Szabadkai G, Wilkins MR, Wojciak-Stothard B. Intracellular Chloride Channels Regulate Endothelial Metabolic Reprogramming in Pulmonary Arterial Hypertension. Am J Respir Cell Mol Biol 2023; 68:103-115. [PMID: 36264759 PMCID: PMC9817916 DOI: 10.1165/rcmb.2022-0111oc] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Mitochondrial fission and a metabolic switch from oxidative phosphorylation to glycolysis are key features of vascular pathology in pulmonary arterial hypertension (PAH) and are associated with exuberant endothelial proliferation and apoptosis. The underlying mechanisms are poorly understood. We describe the contribution of two intracellular chloride channel proteins, CLIC1 and CLIC4, both highly expressed in PAH and cancer, to mitochondrial dysfunction and energy metabolism in PAH endothelium. Pathological overexpression of CLIC proteins induces mitochondrial fragmentation, inhibits mitochondrial cristae formation, and induces metabolic shift toward glycolysis in human pulmonary artery endothelial cells, consistent with changes observed in patient-derived cells. Interactions of CLIC proteins with structural components of the inner mitochondrial membrane offer mechanistic insights. Endothelial CLIC4 excision and mitofusin 2 supplementation have protective effects in human PAH cells and preclinical PAH. This study is the first to demonstrate the key role of endothelial intracellular chloride channels in the regulation of mitochondrial structure, biogenesis, and metabolic reprogramming in expression of the PAH phenotype.
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Affiliation(s)
- Mai M. Alzaydi
- National Heart and Lung Institute,,National Center for Biotechnology, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia
| | - Vahitha B. Abdul-Salam
- National Heart and Lung Institute,,Centre for Cardiovascular Medicine and Device Innovation, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Harry J. Whitwell
- National Phenome Centre and Imperial Clinical Phenotyping Centre, and,Section of Bioanalytical Chemistry, Division of Systems Medicine, Department of Metabolism, Digestion, and Reproduction, and
| | - Giusy Russomanno
- National Heart and Lung Institute,,Medical Research Council (MRC) Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Angelos Glynos
- Mitochondrial Biology Unit, Medical Research Council, University of Cambridge, Cambridge, United Kingdom; and
| | - Daria Capece
- Centre for Cell Signalling and Inflammation, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
| | - Gyorgy Szabadkai
- Cell and Developmental Biology, University College London, London, United Kingdom
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21
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Robertson JO, Erzurum SC, Asosingh K. Pathological Roles for Endothelial Colony-Forming Cells in Neonatal and Adult Lung Disease. Am J Respir Cell Mol Biol 2023; 68:13-22. [PMID: 36215049 PMCID: PMC9817912 DOI: 10.1165/rcmb.2022-0318ps] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 10/10/2022] [Indexed: 02/05/2023] Open
Abstract
Endothelial colony-forming cells (ECFCs) are vascular resident and circulating endothelial cell subtypes with potent angiogenic capacity, a hierarchy of single-cell clonogenic potentials, and the ability to participate in de novo blood vessel formation and endothelial repair. Existing literature regarding ECFCs in neonatal and adult pulmonary diseases is confounded by the study of ambiguously defined "endothelial progenitor cells," which are often not true ECFCs. This review contrasts adult and fetal ECFCs, discusses the effect of prematurity on ECFCs, and examines their different pathological roles in neonatal and adult pulmonary diseases, such as bronchopulmonary dysplasia, congenital diaphragmatic hernia, pulmonary artery hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease. Therapeutic potential is also discussed in light of available preclinical data.
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Affiliation(s)
| | - Serpil C. Erzurum
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Kewal Asosingh
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
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22
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Galkin A, Sitapara R, Clemons B, Garcia E, Kennedy M, Guimond D, Carter LL, Douthitt A, Osterhout R, Gandjeva A, Slee D, Salter-Cid L, Tuder RM, Zisman LS. Inhaled seralutinib exhibits potent efficacy in models of pulmonary arterial hypertension. Eur Respir J 2022; 60:2102356. [PMID: 35680144 PMCID: PMC9724289 DOI: 10.1183/13993003.02356-2021] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 05/20/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND Signalling through platelet-derived growth factor receptor (PDGFR), colony-stimulating factor 1 receptor (CSF1R) and mast/stem cell growth factor receptor kit (c-KIT) plays a critical role in pulmonary arterial hypertension (PAH). We examined the preclinical efficacy of inhaled seralutinib, a unique small-molecule PDGFR/CSF1R/c-KIT kinase inhibitor in clinical development for PAH, in comparison to a proof-of-concept kinase inhibitor, imatinib. METHODS Seralutinib and imatinib potency and selectivity were compared. Inhaled seralutinib pharmacokinetics/pharmacodynamics were studied in healthy rats. Efficacy was evaluated in two rat models of PAH: SU5416/Hypoxia (SU5416/H) and monocrotaline pneumonectomy (MCTPN). Effects on inflammatory/cytokine signalling were examined. PDGFR, CSF1R and c-KIT immunohistochemistry in rat and human PAH lung samples and microRNA (miRNA) analysis in the SU5416/H model were performed. RESULTS Seralutinib potently inhibited PDGFRα/β, CSF1R and c-KIT. Inhaled seralutinib demonstrated dose-dependent inhibition of lung PDGFR and c-KIT signalling and increased bone morphogenetic protein receptor type 2 (BMPR2). Seralutinib improved cardiopulmonary haemodynamic parameters and reduced small pulmonary artery muscularisation and right ventricle hypertrophy in both models. In the SU5416/H model, seralutinib improved cardiopulmonary haemodynamic parameters, restored lung BMPR2 protein levels and decreased N-terminal pro-brain natriuretic peptide (NT-proBNP), more than imatinib. Quantitative immunohistochemistry in human lung PAH samples demonstrated increased PDGFR, CSF1R and c-KIT. miRNA analysis revealed candidates that could mediate seralutinib effects on BMPR2. CONCLUSIONS Inhaled seralutinib was an effective treatment of severe PAH in two animal models, with improved cardiopulmonary haemodynamic parameters, a reduction in NT-proBNP, reverse remodelling of pulmonary vascular pathology and improvement in inflammatory biomarkers. Seralutinib showed greater efficacy compared to imatinib in a preclinical study.
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Affiliation(s)
- Anna Galkin
- Gossamer Bio, Inc., San Diego, CA, USA
- A. Galkin and R. Sitapara contributed equally as first authors
| | - Ravikumar Sitapara
- Gossamer Bio, Inc., San Diego, CA, USA
- The Rensselaer Center for Translational Research Inc., Rensselaer, NY, USA
- A. Galkin and R. Sitapara contributed equally as first authors
| | | | | | | | | | | | | | | | - Aneta Gandjeva
- University of Colorado School of Medicine, Aurora, CO, USA
| | | | | | - Rubin M Tuder
- University of Colorado School of Medicine, Aurora, CO, USA
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23
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Abstract
Endothelial colony-forming cells (ECFCs) are progenitor cells that can give rise to colonies of highly proliferative vascular endothelial cells (ECs) with clonal expansion and in vivo blood vessel-forming potential. More than two decades ago, the identification of ECFCs in human peripheral blood created tremendous opportunities as having a clinically accessible source of autologous ECs could facilitate meaningful therapies with the potential to impact multiple vascular diseases. Nevertheless, until recently, the field of endothelial progenitor cells has been plagued with ambiguities and controversies, and reaching a consensus on the definition of ECFCs has not been straightforward. Moreover, although the basic phenotypical and functional characteristics of cultured ECFCs are now well established, some fundamental questions such as the origin of ECFCs and their physiological roles in health and disease remain incompletely understood. Here, I highlight some critical studies that have shaped our current understanding of ECFCs in humans. Insights into the biological attributes of ECFCs are essential for facilitating the clinical translation of their therapeutic potential.
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Affiliation(s)
- Juan M Melero-Martin
- Department of Cardiac Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
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24
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Anis M, Gonzales J, Halstrom R, Baig N, Humpal C, Demeritte R, Epshtein Y, Jacobson JR, Fraidenburg DR. Non-Muscle MLCK Contributes to Endothelial Cell Hyper-Proliferation through the ERK Pathway as a Mechanism for Vascular Remodeling in Pulmonary Hypertension. Int J Mol Sci 2022; 23:ijms232113641. [PMID: 36362426 PMCID: PMC9654627 DOI: 10.3390/ijms232113641] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/28/2022] [Accepted: 11/01/2022] [Indexed: 11/10/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is characterized by endothelial dysfunction, uncontrolled proliferation and migration of pulmonary arterial endothelial cells leading to increased pulmonary vascular resistance resulting in great morbidity and poor survival. Bone morphogenetic protein receptor II (BMPR2) plays an important role in the pathogenesis of PAH as the most common genetic mutation. Non-muscle myosin light chain kinase (nmMLCK) is an essential component of the cellular cytoskeleton and recent studies have shown that increased nmMLCK activity regulates biological processes in various pulmonary diseases such as asthma and acute lung injury. In this study, we aimed to discover the role of nmMLCK in the proliferation and migration of pulmonary arterial endothelial cells (HPAECs) in the pathogenesis of PAH. We used two cellular models relevant to the pathobiology of PAH including BMPR2 silenced and vascular endothelial growth factor (VEGF) stimulated HPAECs. Both models demonstrated an increase in nmMLCK activity along with a robust increase in cellular proliferation, inflammation, and cellular migration. The upregulated nmMLCK activity was also associated with increased ERK expression pointing towards a potential integral cytoplasmic interaction. Mechanistically, we confirmed that when nmMLCK is inhibited by MLCK selective inhibitor (ML-7), proliferation and migration are attenuated. In conclusion, our results demonstrate that nmMLCK upregulation in association with increased ERK expression may contribute to the pathogenesis of PAHby stimulating cellular proliferation and migration.
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Affiliation(s)
- Mariam Anis
- Northwestern Medical Group, Lake Forest, IL 60045, USA
| | - Janae Gonzales
- Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Rachel Halstrom
- Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Noman Baig
- Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Cat Humpal
- Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Regaina Demeritte
- Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Yulia Epshtein
- Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Jeffrey R. Jacobson
- Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Dustin R. Fraidenburg
- Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
- Correspondence: ; Tel.: +1-312-355-5918
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25
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Potential contribution of early endothelial progenitor cell (eEPC)-to-macrophage switching in the development of pulmonary plexogenic lesion. Respir Res 2022; 23:290. [PMID: 36274148 PMCID: PMC9590182 DOI: 10.1186/s12931-022-02210-7] [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: 08/03/2022] [Accepted: 10/04/2022] [Indexed: 11/12/2022] Open
Abstract
Background Plexiform lesions, which have a dynamic appearance in structure and cellular composition, are the histological hallmark of severe pulmonary arterial hypertension in humans. The pathogenesis of the lesion development remains largely unknown, although it may be related to local inflammation and dysfunction in early progenitor endothelial cells (eEPCs). We tested the hypothesis that eEPCs contribute to the development of plexiform lesions by differentiating into macrophages in the setting of chronic inflammation. Methods The eEPC markers CD133 and VEGFR-2, macrophage lineage marker mannose receptor C-type 1 (MRC1), TNFα and nuclear factor erythroid 2-related factor 2 (Nrf2) in plexiform lesions in a broiler model were determined by immunohistochemistry. eEPCs derived from peripheral blood mononuclear cells were exposed to TNFα, and macrophage differentiation and angiogenic capacity of the cells were evaluated by phagocytotic and Matrigel plug assays, respectively. The role of Nrf2 in eEPC-to-macrophage transition as well as in MRC1 expression was also evaluated. Intratracheal installation of TNFα was conducted to determine the effect of local inflammation on the formation of plexiform lesions. Results Cells composed of the early lesions have a typical eEPC phenotype whereas those in more mature lesions display molecular and morphological characteristics of macrophages. Increased TNFα production in plexiform lesions was observed with lesion progression. In vitro studies showed that chronic TNFα challenge directed eEPCs to macrophage differentiation accompanied by hyperactivation of Nrf2, a stress-responsive transcription factor. Nrf2 activation (Keap1 knockdown) caused a marked downregulation in CD133 but upregulation in MRC1 mRNA. Dual luciferase reporter assay demonstrated that Nrf2 binds to the promoter of MRC1 to trigger its expression. In good agreement with the in vitro observation, TNFα exposure induced macrophage differentiation of eEPCs in Matrigel plugs, resulting in reduced neovascularization of the plugs. Intratracheal installation of TNFα resulted in a significant increase in plexiform lesion density. Conclusions This work provides evidence suggesting that macrophage differentiation of eEPCs resulting from chronic inflammatory stimulation contributes to the development of plexiform lesions. Given the key role of Nrf2 in the phenotypic switching of eEPCs to macrophages, targeting this molecular might be beneficial for intervention of plexiform lesions. Supplementary Information The online version contains supplementary material available at 10.1186/s12931-022-02210-7.
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26
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Functional Impairment of Endothelial Colony Forming Cells (ECFC) in Patients with Severe Atherosclerotic Cardiovascular Disease (ASCVD). Int J Mol Sci 2022; 23:ijms23168969. [PMID: 36012229 PMCID: PMC9409296 DOI: 10.3390/ijms23168969] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/02/2022] [Accepted: 08/09/2022] [Indexed: 11/17/2022] Open
Abstract
Endothelial dysfunction is a key factor in atherosclerosis. However, the link between endothelial repair and severity of atherosclerotic cardiovascular disease (ASCVD) is unclear. This study investigates the relationship between ASCVD, markers of inflammation, and circulating endothelial progenitor cells, namely hematopoietic cells with paracrine angiogenic activity and endothelial colony forming cells (ECFC). Two hundred and forty-three subjects from the TELARTA study were classified according to the presence of clinical atherosclerotic disease. ASCVD severity was assessed by the number of involved vascular territories. Flow cytometry was used to numerate circulating progenitor cells (PC) expressing CD34 and those co-expressing CD45, CD34, and KDR. Peripheral blood mononuclear cells ex vivo culture methods were used to determine ECFC and Colony Forming Unit- endothelial cells (CFU-EC). The ECFC subpopulation was analyzed for proliferation, senescence, and vasculogenic properties. Plasma levels of IL-6 and VEGF-A were measured using Cytokine Array. Despite an increased number of circulating precursors in ASCVD patients, ASCVD impaired the colony forming capacity and the angiogenic properties of ECFC in a severity-dependent manner. Alteration of ECFC was associated with increased senescent phenotype and IL-6 levels. Our study demonstrates a decrease in ECFC repair capacity according to ASCVD severity in an inflammatory and senescence-associated secretory phenotype context.
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27
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Exploring Endothelial Colony-Forming Cells to Better Understand the Pathophysiology of Disease: An Updated Review. Stem Cells Int 2022; 2022:4460041. [PMID: 35615696 PMCID: PMC9126670 DOI: 10.1155/2022/4460041] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 04/20/2022] [Accepted: 05/09/2022] [Indexed: 12/12/2022] Open
Abstract
Endothelial cell (EC) dysfunction has been implicated in a variety of pathological conditions. The collection of ECs from patients is typically conducted postmortem or through invasive procedures, such as surgery and interventional procedures, hampering efforts to clarify the role of ECs in disease onset and progression. In contrast, endothelial colony-forming cells (ECFCs), also termed late endothelial progenitor cells, late outgrowth endothelial cells, blood outgrowth endothelial cells, or endothelial outgrowth cells, are obtained in a minimally invasive manner, namely, by the culture of human peripheral blood mononuclear cells in endothelial growth medium. ECFCs resemble mature ECs phenotypically, genetically, and functionally, making them excellent surrogates for ECs. Numerous studies have been performed that examined ECFC function in conditions such as coronary artery disease, diabetes mellitus, hereditary hemorrhagic telangiectasia, congenital bicuspid aortic valve disease, pulmonary arterial hypertension, venous thromboembolic disease, and von Willebrand disease. Here, we provide an updated review of studies using ECFCs that were performed to better understand the pathophysiology of disease. We also discuss the potential of ECFCs as disease biomarkers and the standardized methods to culture, quantify, and evaluate ECFCs and suggest the future direction of research in this field.
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28
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Smits AJ, Botros L, Mol MA, Ziesemer KA, Wilkins MR, Vonk Noordegraaf A, Bogaard HJ, Aman J. A Systematic Review with Meta-analysis of Biomarkers for detection of Pulmonary Arterial Hypertension. ERJ Open Res 2022; 8:00009-2022. [PMID: 35651362 PMCID: PMC9149393 DOI: 10.1183/23120541.00009-2022] [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: 01/07/2022] [Accepted: 03/04/2022] [Indexed: 11/20/2022] Open
Abstract
Rationale The blood is a rich source of potential biomarkers for the diagnosis of idiopathic and hereditary pulmonary arterial hypertension (iPAH and hPAH, referred to as “PAH”). While a lot of biomarkers have been identified for PAH, the clinical utility of these biomarkers often remains unclear. Here, we performed an unbiased meta-analysis of published biomarkers to identify biomarkers with the highest performance for detection of PAH. Methods A literature search (in PubMed, Embase.com, Clarivate Analytics/Web of Science Core Collection and Wiley/Cochrane Library) was performed up to 28 January 2021. Primary end points were blood biomarker levels in PAH versus asymptomatic controls or patients suspected of pulmonary hypertension (PH) with proven normal haemodynamic profiles. Results 149 articles were identified by the literature search. Meta-analysis of 26 biomarkers yielded 17 biomarkers that were differentially expressed in PAH and non-PH control subjects. Red cell distribution width, low density lipid-cholesterol, d-dimer, N-terminal prohormone of brain natriuretic protein (NT-proBNP), interleukin-6 (IL-6) and uric acid were biomarkers with the largest observed differences, largest sample sizes and a low risk of publication bias. Receiver operating characteristic curves and sensitivity/specificity analyses demonstrated that NT-proBNP had a high sensitivity, but low specificity for PAH. For the other biomarkers, insufficient data on diagnostic accuracy with receiver operating characteristic curves were available for meta-analysis. Conclusion This meta-analysis validates NT-proBNP as a biomarker with high sensitivity for PAH, albeit with low specificity. The majority of biomarkers evaluated in this meta-analysis lacked either external validation or data on diagnostic accuracy. Further validation studies are required as well as studies that test combinations of biomarkers to improve specificity. Meta-analysis of 26 biomarkers yielded 17 differentially expressed biomarkers in PAH. NT-proBNP had the highest diagnostic accuracy but had a low specificity for PAH. Other markers, including IL-6, RDW, LDL-c, D-dimer and UA, lacked clinical validation.https://bit.ly/3J4YAyC
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29
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Sun QW, Sun Z. Stem Cell Therapy for Pulmonary Arterial Hypertension: An Update. J Heart Lung Transplant 2022; 41:692-703. [DOI: 10.1016/j.healun.2022.02.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 02/04/2022] [Accepted: 02/27/2022] [Indexed: 10/18/2022] Open
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30
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Frantz RP, Benza RL, Channick RN, Chin K, Howard LS, McLaughlin VV, Sitbon O, Zamanian RT, Hemnes AR, Cravets M, Bruey JM, Roscigno R, Mottola D, Elman E, Zisman LS, Ghofrani HA. TORREY, a Phase 2 study to evaluate the efficacy and safety of inhaled seralutinib for the treatment of pulmonary arterial hypertension. Pulm Circ 2021; 11:20458940211057071. [PMID: 34790348 PMCID: PMC8591655 DOI: 10.1177/20458940211057071] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 10/12/2021] [Indexed: 12/14/2022] Open
Abstract
Aberrant kinase signaling that involves platelet-derived growth factor receptor (PDGFR) α/β, colony stimulating factor 1 receptor (CSF1R), and stem cell factor receptor (c-KIT) pathways may be responsible for vascular remodeling in pulmonary arterial hypertension. Targeting these specific pathways may potentially reverse the pathological inflammation, cellular proliferation, and fibrosis associated with pulmonary arterial hypertension progression. Seralutinib (formerly known as GB002) is a novel, potent, clinical stage inhibitor of PDGFRα/β, CSF1R, and c-KIT delivered via inhalation that is being developed for patients with pulmonary arterial hypertension. Here, we report on an ongoing Phase 2 randomized, double-blind, placebo-controlled trial (NCT04456998) evaluating the efficacy and safety of seralutinib in subjects with World Health Organization Group 1 Pulmonary Hypertension who are classified as Functional Class II or III. A total of 80 subjects will be enrolled and randomized to receive either study drug or placebo for 24 weeks followed by an optional 72-week open-label extension study. The primary endpoint is the change from baseline to Week 24 in pulmonary vascular resistance by right heart catheterization. The secondary endpoint is the change in distance from baseline to Week 24 achieved in the 6-min walk test. A computerized tomography sub-study will examine the effect of seralutinib on pulmonary vascular remodelling. A separate heart rate monitoring sub-study will examine the effect of seralutinib on cardiac effort during the 6-min walk test.
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Affiliation(s)
| | | | | | - Kelly Chin
- UT Southwestern Medical Center, Dallas, TX, USA
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31
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Qin K, Lei J, Yang J. The Differentiation of Pluripotent Stem Cells towards Endothelial Progenitor Cells - Potential Application in Pulmonary Arterial Hypertension. Int J Stem Cells 2021; 15:122-135. [PMID: 34711697 PMCID: PMC9148829 DOI: 10.15283/ijsc21044] [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: 03/07/2021] [Revised: 08/26/2021] [Accepted: 09/02/2021] [Indexed: 11/22/2022] Open
Abstract
Background and Objectives Endothelial progenitor cells (EPCs) and endothelial cells (ECs) have been applied in the clinic to treat pulmonary arterial hypertension (PAH), a disease characterized by disordered pulmonary vasculature. However, the lack of sufficient transplantable cells before the deterioration of disease condition is a current limitation to apply cell therapy in patients. It is necessary to differentiate pluripotent stem cells (PSCs) into EPCs and identify their characteristics. Methods and Results Comparing previously reported methods of human PSCs-derived ECs, we optimized a highly efficient differentiation protocol to obtain cells that match the phenotype of isolated EPCs from healthy donors. The protocol is compatible with chemically defined medium (CDM), it could produce a large number of clinically applicable cells with low cost. Moreover, we also found PSCs-derived EPCs express CD133, have some characteristics of mesenchymal stem cells and are capable of homing to repair blood vessels in zebrafish xenograft assays. In addition, we further revealed that IPAH PSCs-derived EPCs have higher expression of proliferation-related genes and lower expression of immune-related genes than normal EPCs and PSCs-derived EPCs through microarray analysis. Conclusions In conclusion, we optimized a highly efficient differentiation protocol to obtain PSCs-derived EPCs with the phenotypic and molecular characteristics of EPCs from healthy donors which distinguished them from EPCs from PAH.
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Affiliation(s)
- Kezhou Qin
- Department of Cell Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jia Lei
- Department of Physiology, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jun Yang
- Department of Cell Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Department of Physiology, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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32
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Evans CE, Cober ND, Dai Z, Stewart DJ, Zhao YY. Endothelial cells in the pathogenesis of pulmonary arterial hypertension. Eur Respir J 2021; 58:13993003.03957-2020. [PMID: 33509961 DOI: 10.1183/13993003.03957-2020] [Citation(s) in RCA: 161] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 01/13/2021] [Indexed: 12/11/2022]
Abstract
Pulmonary arterial hypertension (PAH) is a devastating disease that involves pulmonary vasoconstriction, small vessel obliteration, large vessel thickening and obstruction, and development of plexiform lesions. PAH vasculopathy leads to progressive increases in pulmonary vascular resistance, right heart failure and, ultimately, premature death. Besides other cell types that are known to be involved in PAH pathogenesis (e.g. smooth muscle cells, fibroblasts and leukocytes), recent studies have demonstrated that endothelial cells (ECs) have a crucial role in the initiation and progression of PAH. The EC-specific role in PAH is multi-faceted and affects numerous pathophysiological processes, including vasoconstriction, inflammation, coagulation, metabolism and oxidative/nitrative stress, as well as cell viability, growth and differentiation. In this review, we describe how EC dysfunction and cell signalling regulate the pathogenesis of PAH. We also highlight areas of research that warrant attention in future studies, and discuss potential molecular signalling pathways in ECs that could be targeted therapeutically in the prevention and treatment of PAH.
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Affiliation(s)
- Colin E Evans
- Program for Lung and Vascular Biology, Section of Injury Repair and Regeneration, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.,Dept of Pediatrics, Division of Critical Care, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Nicholas D Cober
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.,Dept of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Zhiyu Dai
- Program for Lung and Vascular Biology, Section of Injury Repair and Regeneration, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.,Dept of Pediatrics, Division of Critical Care, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.,Dept of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, USA
| | - Duncan J Stewart
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.,Dept of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - You-Yang Zhao
- Program for Lung and Vascular Biology, Section of Injury Repair and Regeneration, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA .,Dept of Pediatrics, Division of Critical Care, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.,Dept of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.,Dept of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.,Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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33
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Novoyatleva T, Rai N, Kojonazarov B, Veeroju S, Ben-Batalla I, Caruso P, Shihan M, Presser N, Götz E, Lepper C, Herpel S, Manaud G, Perros F, Gall H, Ghofrani HA, Weissmann N, Grimminger F, Wharton J, Wilkins M, Upton PD, Loges S, Morrell NW, Seeger W, Schermuly RT. Deficiency of Axl aggravates pulmonary arterial hypertension via BMPR2. Commun Biol 2021; 4:1002. [PMID: 34429509 PMCID: PMC8385080 DOI: 10.1038/s42003-021-02531-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 08/05/2021] [Indexed: 11/16/2022] Open
Abstract
Pulmonary arterial hypertension (PAH), is a fatal disease characterized by a pseudo-malignant phenotype. We investigated the expression and the role of the receptor tyrosine kinase Axl in experimental (i.e., monocrotaline and Su5416/hypoxia treated rats) and clinical PAH. In vitro Axl inhibition by R428 and Axl knock-down inhibited growth factor-driven proliferation and migration of non-PAH and PAH PASMCs. Conversely, Axl overexpression conferred a growth advantage. Axl declined in PAECs of PAH patients. Axl blockage inhibited BMP9 signaling and increased PAEC apoptosis, while BMP9 induced Axl phosphorylation. Gas6 induced SMAD1/5/8 phosphorylation and ID1/ID2 increase were blunted by BMP signaling obstruction. Axl association with BMPR2 was facilitated by Gas6/BMP9 stimulation and diminished by R428. In vivo R428 aggravated right ventricular hypertrophy and dysfunction, abrogated BMPR2 signaling, elevated pulmonary endothelial cell apoptosis and loss. Together, Axl is a key regulator of endothelial BMPR2 signaling and potential determinant of PAH.
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Affiliation(s)
- Tatyana Novoyatleva
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany.
| | - Nabham Rai
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany
| | - Baktybek Kojonazarov
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany
- Institute for Lung Health, Giessen, Germany
| | - Swathi Veeroju
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany
| | - Isabel Ben-Batalla
- Department of Oncology, Hematology and Bone Marrow Transplantation with section Pneumology, Hubertus Wald University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Paola Caruso
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - Mazen Shihan
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany
| | - Nadine Presser
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany
| | - Elsa Götz
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany
| | - Carina Lepper
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany
| | - Sebastian Herpel
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany
| | - Grégoire Manaud
- Université Paris-Saclay, AP-HP, INSERM UMR_S 999, Service de Pneumologie et Soins Intensifs Respiratoires, Hôpital de Bicêtre, Le Kremlin Bicêtre, France
| | - Frédéric Perros
- Université Paris-Saclay, AP-HP, INSERM UMR_S 999, Service de Pneumologie et Soins Intensifs Respiratoires, Hôpital de Bicêtre, Le Kremlin Bicêtre, France
| | - Henning Gall
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany
| | - Hossein Ardeschir Ghofrani
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany
| | - Norbert Weissmann
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany
| | - Friedrich Grimminger
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany
| | - John Wharton
- Centre for Pharmacology and Therapeutics, Department of Medicine, Imperial College London, London, UK
| | - Martin Wilkins
- Centre for Pharmacology and Therapeutics, Department of Medicine, Imperial College London, London, UK
| | - Paul D Upton
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - Sonja Loges
- Department of Oncology, Hematology and Bone Marrow Transplantation with section Pneumology, Hubertus Wald University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Werner Seeger
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany
- Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Ralph T Schermuly
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany.
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34
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Morphological and functional alterations in endothelial colony-forming cells from recovered COVID-19 patients. Thromb Res 2021; 206:55-59. [PMID: 34411875 PMCID: PMC8363179 DOI: 10.1016/j.thromres.2021.08.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 08/06/2021] [Accepted: 08/10/2021] [Indexed: 01/27/2023]
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Clinically compatible advances in blood-derived endothelial progenitor cell isolation and reprogramming for translational applications. N Biotechnol 2021; 63:1-9. [PMID: 33588094 DOI: 10.1016/j.nbt.2021.02.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 01/27/2021] [Accepted: 02/07/2021] [Indexed: 11/21/2022]
Abstract
The promise of using induced pluripotent stem cells (iPSCs) for cellular therapies has been hampered by the lack of easily isolatable and well characterized source cells whose genomes have undergone minimal changes during their processing. Blood-derived late-outgrowth endothelial progenitor cells (EPCs) are used for disease modeling and have potential therapeutic uses including cell transplantation and the translation of induced pluripotent stem cell (iPSC) derivatives. However, the current isolation of EPCs has been inconsistent and requires at least 40-80 mL of blood, limiting their wider use. In addition, previous EPC reprogramming methods precluded the translation of EPC-derived iPSCs to the clinic. Here a series of clinically-compatible advances in the isolation and reprogramming of EPCs is presented, including a reduction of blood sampling volumes to 10 mL and use of highly efficient RNA-based reprogramming methods together with autologous human serum, resulting in clinically relevant iPSCs carrying minimal copy number variations (CNVs) compared to their parent line.
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36
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Dierick F, Solinc J, Bignard J, Soubrier F, Nadaud S. Progenitor/Stem Cells in Vascular Remodeling during Pulmonary Arterial Hypertension. Cells 2021; 10:cells10061338. [PMID: 34071347 PMCID: PMC8226806 DOI: 10.3390/cells10061338] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 05/12/2021] [Accepted: 05/21/2021] [Indexed: 12/18/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is characterized by an important occlusive vascular remodeling with the production of new endothelial cells, smooth muscle cells, myofibroblasts, and fibroblasts. Identifying the cellular processes leading to vascular proliferation and dysfunction is a major goal in order to decipher the mechanisms leading to PAH development. In addition to in situ proliferation of vascular cells, studies from the past 20 years have unveiled the role of circulating and resident vascular in pulmonary vascular remodeling. This review aims at summarizing the current knowledge on the different progenitor and stem cells that have been shown to participate in pulmonary vascular lesions and on the pathways regulating their recruitment during PAH. Finally, this review also addresses the therapeutic potential of circulating endothelial progenitor cells and mesenchymal stem cells.
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Affiliation(s)
- France Dierick
- Lady Davis Institute for Medical Research, McGill University, Montréal, QC H3T 1E2, Canada;
| | - Julien Solinc
- UMR_S 1166, Faculté de Médecine Pitié-Salpêtrière, INSERM, Sorbonne Université, 75013 Paris, France; (J.S.); (J.B.); (F.S.)
| | - Juliette Bignard
- UMR_S 1166, Faculté de Médecine Pitié-Salpêtrière, INSERM, Sorbonne Université, 75013 Paris, France; (J.S.); (J.B.); (F.S.)
| | - Florent Soubrier
- UMR_S 1166, Faculté de Médecine Pitié-Salpêtrière, INSERM, Sorbonne Université, 75013 Paris, France; (J.S.); (J.B.); (F.S.)
| | - Sophie Nadaud
- UMR_S 1166, Faculté de Médecine Pitié-Salpêtrière, INSERM, Sorbonne Université, 75013 Paris, France; (J.S.); (J.B.); (F.S.)
- Correspondence:
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37
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Sun XQ, Peters EL, Schalij I, Axelsen JB, Andersen S, Kurakula K, Gomez-Puerto MC, Szulcek R, Pan X, da Silva Goncalves Bos D, Schiepers REJ, Andersen A, Goumans MJ, Vonk Noordegraaf A, van der Laarse WJ, de Man FS, Bogaard HJ. Increased MAO-A Activity Promotes Progression of Pulmonary Arterial Hypertension. Am J Respir Cell Mol Biol 2021; 64:331-343. [PMID: 33264068 DOI: 10.1165/rcmb.2020-0105oc] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Monoamine oxidases (MAOs), a class of enzymes bound to the outer mitochondrial membrane, are important sources of reactive oxygen species. Increased MAO-A activity in endothelial cells and cardiomyocytes contributes to vascular dysfunction and progression of left heart failure. We hypothesized that inhibition of MAO-A can be used to treat pulmonary arterial hypertension (PAH) and right ventricular (RV) failure. MAO-A levels in lung and RV samples from patients with PAH were compared with levels in samples from donors without PAH. Experimental PAH was induced in male Sprague-Dawley rats by using Sugen 5416 and hypoxia (SuHx), and RV failure was induced in male Wistar rats by using pulmonary trunk banding (PTB). Animals were randomized to receive either saline or the MAO-A inhibitor clorgyline at 10 mg/kg. Echocardiography and RV catheterization were performed, and heart and lung tissues were collected for further analysis. We found increased MAO-A expression in the pulmonary vasculature of patients with PAH and in experimental experimental PAH induced by SuHx. Cardiac MAO-A expression and activity was increased in SuHx- and PTB-induced RV failure. Clorgyline treatment reduced RV afterload and pulmonary vascular remodeling in SuHx rats through reduced pulmonary vascular proliferation and oxidative stress. Moreover, clorgyline improved RV stiffness and relaxation and reversed RV hypertrophy in SuHx rats. In PTB rats, clorgyline had no direct clorgyline had no direct effect on the right ventricle effect. Our study reveals the role of MAO-A in the progression of PAH. Collectively, these findings indicated that MAO-A may be involved in pulmonary vascular remodeling and consecutive RV failure.
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Affiliation(s)
- Xiao-Qing Sun
- Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences Research Institute, and
| | - Eva L Peters
- Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences Research Institute, and.,Amsterdam University Medical Center, Department of Physiology, Free University, Amsterdam, the Netherlands
| | - Ingrid Schalij
- Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences Research Institute, and
| | - Julie Birkmose Axelsen
- Institute of Clinical Medicine, Department of Cardiology, Aarhus University Hospital, Aarhus University, Aarhus, Denmark; and
| | - Stine Andersen
- Institute of Clinical Medicine, Department of Cardiology, Aarhus University Hospital, Aarhus University, Aarhus, Denmark; and
| | - Kondababu Kurakula
- Laboratory for Cardiovascular Cell Biology, Department of Cell and Chemical Biology
| | - Maria Catalina Gomez-Puerto
- Department of Cell and Chemical Biology, Leiden University Medical Center, and.,Oncode Institute, Leiden University-Oncode Institute, Leiden, the Netherlands
| | - Robert Szulcek
- Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences Research Institute, and
| | - Xiaoke Pan
- Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences Research Institute, and
| | | | - Roy E J Schiepers
- Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences Research Institute, and
| | - Asger Andersen
- Institute of Clinical Medicine, Department of Cardiology, Aarhus University Hospital, Aarhus University, Aarhus, Denmark; and
| | - Marie-José Goumans
- Laboratory for Cardiovascular Cell Biology, Department of Cell and Chemical Biology
| | - Anton Vonk Noordegraaf
- Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences Research Institute, and
| | - Willem J van der Laarse
- Amsterdam University Medical Center, Department of Physiology, Free University, Amsterdam, the Netherlands
| | - Frances S de Man
- Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences Research Institute, and
| | - Harm Jan Bogaard
- Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences Research Institute, and
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38
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Macias D, Moore S, Crosby A, Southwood M, Du X, Tan H, Xie S, Vassallo A, Wood AJT, Wallace EM, Cowburn AS. Targeting HIF2α-ARNT hetero-dimerisation as a novel therapeutic strategy for pulmonary arterial hypertension. Eur Respir J 2021; 57:13993003.02061-2019. [PMID: 32972983 PMCID: PMC7930471 DOI: 10.1183/13993003.02061-2019] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 08/26/2020] [Indexed: 12/13/2022]
Abstract
Pulmonary arterial hypertension (PAH) is a destructive disease of the pulmonary vasculature often leading to right heart failure and death. Current therapeutic intervention strategies only slow disease progression. The role of aberrant hypoxia-inducible factor (HIF)2α stability and function in the initiation and development of pulmonary hypertension (PH) has been an area of intense interest for nearly two decades.Here we determine the effect of a novel HIF2α inhibitor (PT2567) on PH disease initiation and progression, using two pre-clinical models of PH. Haemodynamic measurements were performed, followed by collection of heart, lung and blood for pathological, gene expression and biochemical analysis. Blood outgrowth endothelial cells from idiopathic PAH patients were used to determine the impact of HIF2α-inhibition on endothelial function.Global inhibition of HIF2a reduced pulmonary vascular haemodynamics and pulmonary vascular remodelling in both su5416/hypoxia prevention and intervention models. PT2567 intervention reduced the expression of PH-associated target genes in both lung and cardiac tissues and restored plasma nitrite concentration. Treatment of monocrotaline-exposed rodents with PT2567 reduced the impact on cardiovascular haemodynamics and promoted a survival advantage. In vitro, loss of HIF2α signalling in human pulmonary arterial endothelial cells suppresses target genes associated with inflammation, and PT2567 reduced the hyperproliferative phenotype and overactive arginase activity in blood outgrowth endothelial cells from idiopathic PAH patients. These data suggest that targeting HIF2α hetero-dimerisation with an orally bioavailable compound could offer a new therapeutic approach for PAH. Future studies are required to determine the role of HIF in the heterogeneous PAH population.
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Affiliation(s)
- David Macias
- CRUK Cambridge Centre Early Detection Programme, Dept of Oncology, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK.,Both authors contributed equally
| | - Stephen Moore
- Dept of Medicine, University of Cambridge, Cambridge, UK.,Both authors contributed equally
| | - Alexi Crosby
- Dept of Medicine, University of Cambridge, Cambridge, UK
| | - Mark Southwood
- Dept of Pathology, Papworth Hospital National Health Service Foundation Trust, Cambridge, UK
| | - Xinlin Du
- Peloton Therapeutics Inc. (a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA), Dallas, TX, USA
| | - Huiling Tan
- Peloton Therapeutics Inc. (a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA), Dallas, TX, USA
| | - Shanhai Xie
- Peloton Therapeutics Inc. (a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA), Dallas, TX, USA
| | | | | | - Eli M Wallace
- Peloton Therapeutics Inc. (a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA), Dallas, TX, USA
| | - Andrew S Cowburn
- Dept of Medicine, University of Cambridge, Cambridge, UK .,National Heart and Lung Institute, Imperial College London, London, UK
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39
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Goten C, Usui S, Takashima SI, Inoue O, Okada H, Shimojima M, Sakata K, Kawashiri M, Kaneko S, Takamura M. Circulating nerve growth factor receptor positive cells are associated with severity and prognosis of pulmonary arterial hypertension. Pulm Circ 2021; 11:2045894021990525. [PMID: 33767850 PMCID: PMC7953227 DOI: 10.1177/2045894021990525] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 01/06/2021] [Indexed: 12/13/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) remains a disease with a poor prognosis, so
early detection and treatment are very important. Sensitive and non-invasive
markers for PAH are urgently required. This study was performed to identify
sensitive markers of the clinical severity and prognosis of PAH. Patients
diagnosed with PAH (n = 30) and control participants (n = 15) were enrolled in
this observational study. Major EPC and MSC markers (including CD34, CD133,
VEGFR2, CD90, PDGFRα, and NGFR) in peripheral blood mononuclear cells (PBMNCs)
were assessed by flow cytometry. Associations of these markers with hemodynamic
parameters (e.g. mean pulmonary arterial pressure, pulmonary vascular
resistance, and cardiac index) were assessed. Patients with PAH were followed up
for 12 months to assess the incidence of major adverse events, defined as death
or lung transplantation. Levels of circulating EPC and MSC markers in PBMNCs
were higher in patients with PAH than in control participants. Among the studied
markers, nerve growth factor receptor (NGFR) was significantly positively
correlated with hemodynamic parameters. During the 12-month follow-up period,
major-event-free survival was significantly higher in patients with PAH who had
relatively low frequencies of NGFR positive cells than patients who had higher
frequencies. These results suggested that the presence of circulating NGFR
positive cells among PBMNCs may be a novel biomarker for the severity and
prognosis of PAH.
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Affiliation(s)
- Chiaki Goten
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.,Department of System Biology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| | - Soichiro Usui
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| | - Shin-Ichiro Takashima
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| | - Oto Inoue
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| | - Hirofumi Okada
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| | - Masaya Shimojima
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| | - Kenji Sakata
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| | - Masaaki Kawashiri
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| | - Shuichi Kaneko
- Department of System Biology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| | - Masayuki Takamura
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
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40
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Kearney K, Kotlyar E, Lau EMT. Pulmonary Vascular Disease as a Systemic and Multisystem Disease. Clin Chest Med 2021; 42:167-177. [PMID: 33541610 DOI: 10.1016/j.ccm.2020.11.001] [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: 02/08/2023]
Abstract
Pulmonary arterial hypertension (PAH) is a disease of progressive pulmonary vascular remodeling due to abnormal proliferation of pulmonary vascular endothelial and smooth muscle cells and endothelial dysfunction. PAH is a multisystem disease with systemic manifestations and complications. This article covers the chronic heart failure syndrome, including the systemic consequences of right ventricle-pulmonary artery uncoupling and neurohormonal activation, skeletal and respiratory muscle effects, systemic endothelial dysfunction and coronary artery disease, systemic inflammation and infection, endocrine and metabolic changes, the liver and gut axis, sleep, neurologic complications, and skin and iron metabolic changes.
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Affiliation(s)
- Katherine Kearney
- Cardiology Department, St Vincent's Hospital, 394 Victoria Street, Darlinghurst, New South Wales 2010, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, Australia
| | - Eugene Kotlyar
- St Vincent's Clinical School, University of New South Wales, Sydney, Australia; Heart Transplant Unit, St Vincent's Hospital, 394 Victoria Street, Darlinghurst, New South Wales 2010, Australia
| | - Edmund M T Lau
- Department of Respiratory Medicine, Royal Prince Alfred Hospital, Missenden Road, Camperdown, New South Wales 2050, Australia; Sydney Medical School, University of Sydney, Camperdown, Australia.
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41
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Liang S, Desai AA, Black SM, Tang H. Cytokines, Chemokines, and Inflammation in Pulmonary Arterial Hypertension. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1303:275-303. [PMID: 33788198 DOI: 10.1007/978-3-030-63046-1_15] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
According to the World Symposium Pulmonary Hypertension (WSPH) classification, pulmonary hypertension (PH) is classified into five categories based on etiology. Among them, Group 1 pulmonary arterial hypertension (PAH) disorders are rare but progressive and often, fatal despite multiple approved treatments. Elevated pulmonary arterial pressure in patients with WSPH Group 1 PAH is mainly caused by increased pulmonary vascular resistance (PVR), due primarily to sustained pulmonary vasoconstriction and excessive obliterative pulmonary vascular remodeling. Growing evidence indicates that inflammation plays a critical role in the development of pulmonary vascular remodeling associated with PAH. While the role of auto-immunity is unclear, infiltration of inflammatory cells in and around vascular lesions, including T- and B-cells, dendritic cells, macrophages, and mast cells have been observed in PAH patients. Serum and plasma levels of chemokines, cytokines, and autoantibodies are also increased in PAH patients; some of these circulating molecules are correlated with disease severity and survival. Preclinical experiments have reported a key role of the inflammation in PAH pathophysiology in vivo. Importantly, anti-inflammatory and immunosuppressive agents have further exhibited therapeutic effects. The present chapter reviews published experimental and clinical evidence highlighting the canonical role of inflammation in the pathogenesis of PAH and as a major target for the development of anti-inflammatory therapies in patients with PAH.
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Affiliation(s)
- Shuxin Liang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.,State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Ankit A Desai
- Department of Medicine, Indiana University, Indianapolis, IN, USA
| | - Stephen M Black
- Division of Translational and Regenerative Medicine, College of Medicine, University of Arizona, Tucson, AZ, USA
| | - Haiyang Tang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China. .,State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
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Swietlik EM, Prapa M, Martin JM, Pandya D, Auckland K, Morrell NW, Gräf S. 'There and Back Again'-Forward Genetics and Reverse Phenotyping in Pulmonary Arterial Hypertension. Genes (Basel) 2020; 11:E1408. [PMID: 33256119 PMCID: PMC7760524 DOI: 10.3390/genes11121408] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 11/17/2020] [Accepted: 11/23/2020] [Indexed: 02/07/2023] Open
Abstract
Although the invention of right heart catheterisation in the 1950s enabled accurate clinical diagnosis of pulmonary arterial hypertension (PAH), it was not until 2000 when the landmark discovery of the causative role of bone morphogenetic protein receptor type II (BMPR2) mutations shed new light on the pathogenesis of PAH. Since then several genes have been discovered, which now account for around 25% of cases with the clinical diagnosis of idiopathic PAH. Despite the ongoing efforts, in the majority of patients the cause of the disease remains elusive, a phenomenon often referred to as "missing heritability". In this review, we discuss research approaches to uncover the genetic architecture of PAH starting with forward phenotyping, which in a research setting should focus on stable intermediate phenotypes, forward and reverse genetics, and finally reverse phenotyping. We then discuss potential sources of "missing heritability" and how functional genomics and multi-omics methods are employed to tackle this problem.
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Affiliation(s)
- Emilia M. Swietlik
- Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; (E.M.S.); (M.P.); (J.M.M.); (D.P.); (K.A.); (N.W.M.)
- Royal Papworth Hospital NHS Foundation Trust, Cambridge CB2 0AY, UK
- Addenbrooke’s Hospital NHS Foundation Trust, Cambridge CB2 0QQ, UK
| | - Matina Prapa
- Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; (E.M.S.); (M.P.); (J.M.M.); (D.P.); (K.A.); (N.W.M.)
- Addenbrooke’s Hospital NHS Foundation Trust, Cambridge CB2 0QQ, UK
| | - Jennifer M. Martin
- Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; (E.M.S.); (M.P.); (J.M.M.); (D.P.); (K.A.); (N.W.M.)
| | - Divya Pandya
- Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; (E.M.S.); (M.P.); (J.M.M.); (D.P.); (K.A.); (N.W.M.)
| | - Kathryn Auckland
- Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; (E.M.S.); (M.P.); (J.M.M.); (D.P.); (K.A.); (N.W.M.)
| | - Nicholas W. Morrell
- Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; (E.M.S.); (M.P.); (J.M.M.); (D.P.); (K.A.); (N.W.M.)
- Royal Papworth Hospital NHS Foundation Trust, Cambridge CB2 0AY, UK
- Addenbrooke’s Hospital NHS Foundation Trust, Cambridge CB2 0QQ, UK
- NIHR BioResource for Translational Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
| | - Stefan Gräf
- Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; (E.M.S.); (M.P.); (J.M.M.); (D.P.); (K.A.); (N.W.M.)
- NIHR BioResource for Translational Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK
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Pu X, Du L, Hu Y, Fan Y, Xu Q. Stem/Progenitor Cells and Pulmonary Arterial Hypertension. Arterioscler Thromb Vasc Biol 2020; 41:167-178. [PMID: 33028095 DOI: 10.1161/atvbaha.120.315052] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by endothelial dysfunction and vascular remodeling. Despite significant advancement in our understanding of the pathogenesis of PAH in recent years, treatment options for PAH are limited and their prognosis remains poor. PAH is now seen as a severe pulmonary arterial vasculopathy with structural changes driven by excessive vascular proliferation and inflammation. Perturbations of a number of cellular and molecular mechanisms have been described, including pathways involving growth factors, cytokines, metabolic signaling, elastases, and proteases, underscoring the complexity of the disease pathogenesis. Interestingly, emerging evidence suggests that stem/progenitor cells may have an impact on disease development and therapy. In preclinical studies, stem/progenitor cells displayed an ability to promote endothelial repair of dysfunctional arteries and induce neovascularization. The stem cell-based therapy for PAH are now under active investigation. This review article will briefly summarize the updates in the research field, with a special focus on the contribution of stem/progenitor cells to lesion formation via influencing vascular cell functions and highlight the potential clinical application of stem/progenitor cell therapy to PAH.
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Affiliation(s)
- Xiangyuan Pu
- Department of Cardiology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China (X.P., L.D., Y.H., Q.X.)
| | - Luping Du
- Department of Cardiology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China (X.P., L.D., Y.H., Q.X.)
| | - Yanhua Hu
- Department of Cardiology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China (X.P., L.D., Y.H., Q.X.)
| | - Ye Fan
- Department of Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Chongqing, China (Y.F.)
| | - Qingbo Xu
- Department of Cardiology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China (X.P., L.D., Y.H., Q.X.)
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Therapeutic Potential of Endothelial Colony-Forming Cells in Ischemic Disease: Strategies to Improve their Regenerative Efficacy. Int J Mol Sci 2020; 21:ijms21197406. [PMID: 33036489 PMCID: PMC7582994 DOI: 10.3390/ijms21197406] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 10/02/2020] [Accepted: 10/02/2020] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular disease (CVD) comprises a range of major clinical cardiac and circulatory diseases, which produce immense health and economic burdens worldwide. Currently, vascular regenerative surgery represents the most employed therapeutic option to treat ischemic disorders, even though not all the patients are amenable to surgical revascularization. Therefore, more efficient therapeutic approaches are urgently required to promote neovascularization. Therapeutic angiogenesis represents an emerging strategy that aims at reconstructing the damaged vascular network by stimulating local angiogenesis and/or promoting de novo blood vessel formation according to a process known as vasculogenesis. In turn, circulating endothelial colony-forming cells (ECFCs) represent truly endothelial precursors, which display high clonogenic potential and have the documented ability to originate de novo blood vessels in vivo. Therefore, ECFCs are regarded as the most promising cellular candidate to promote therapeutic angiogenesis in patients suffering from CVD. The current briefly summarizes the available information about the origin and characterization of ECFCs and then widely illustrates the preclinical studies that assessed their regenerative efficacy in a variety of ischemic disorders, including acute myocardial infarction, peripheral artery disease, ischemic brain disease, and retinopathy. Then, we describe the most common pharmacological, genetic, and epigenetic strategies employed to enhance the vasoreparative potential of autologous ECFCs by manipulating crucial pro-angiogenic signaling pathways, e.g., extracellular-signal regulated kinase/Akt, phosphoinositide 3-kinase, and Ca2+ signaling. We conclude by discussing the possibility of targeting circulating ECFCs to rescue their dysfunctional phenotype and promote neovascularization in the presence of CVD.
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Theilmann AL, Hawke LG, Hilton LR, Whitford MKM, Cole DV, Mackeil JL, Dunham-Snary KJ, Mewburn J, James PD, Maurice DH, Archer SL, Ormiston ML. Endothelial BMPR2 Loss Drives a Proliferative Response to BMP (Bone Morphogenetic Protein) 9 via Prolonged Canonical Signaling. Arterioscler Thromb Vasc Biol 2020; 40:2605-2618. [PMID: 32998516 PMCID: PMC7571847 DOI: 10.1161/atvbaha.119.313357] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Supplemental Digital Content is available in the text. Pulmonary arterial hypertension is a disease of proliferative vascular occlusion that is strongly linked to mutations in BMPR2—the gene encoding the BMPR-II (BMP [bone morphogenetic protein] type II receptor). The endothelial-selective BMPR-II ligand, BMP9, reverses disease in animal models of pulmonary arterial hypertension and suppresses the proliferation of healthy endothelial cells. However, the impact of BMPR2 loss on the antiproliferative actions of BMP9 has yet to be assessed.
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Affiliation(s)
- Anne L Theilmann
- Department of Biomedical and Molecular Sciences (A.L.T., L.G.H., L.R.H., M.K.M.W., D.V.C., J.L.M., D.H.M., M.L.O.), Queen's University, Kingston, Canada
| | - Lindsey G Hawke
- Department of Biomedical and Molecular Sciences (A.L.T., L.G.H., L.R.H., M.K.M.W., D.V.C., J.L.M., D.H.M., M.L.O.), Queen's University, Kingston, Canada
| | - L Rhiannon Hilton
- Department of Biomedical and Molecular Sciences (A.L.T., L.G.H., L.R.H., M.K.M.W., D.V.C., J.L.M., D.H.M., M.L.O.), Queen's University, Kingston, Canada
| | - Mara K M Whitford
- Department of Biomedical and Molecular Sciences (A.L.T., L.G.H., L.R.H., M.K.M.W., D.V.C., J.L.M., D.H.M., M.L.O.), Queen's University, Kingston, Canada
| | - Devon V Cole
- Department of Biomedical and Molecular Sciences (A.L.T., L.G.H., L.R.H., M.K.M.W., D.V.C., J.L.M., D.H.M., M.L.O.), Queen's University, Kingston, Canada
| | - Jodi L Mackeil
- Department of Biomedical and Molecular Sciences (A.L.T., L.G.H., L.R.H., M.K.M.W., D.V.C., J.L.M., D.H.M., M.L.O.), Queen's University, Kingston, Canada
| | - Kimberly J Dunham-Snary
- Department of Medicine (K.J.D.-S., J.M., P.D.J., S.L.A., M.L.O.), Queen's University, Kingston, Canada
| | - Jeffrey Mewburn
- Department of Medicine (K.J.D.-S., J.M., P.D.J., S.L.A., M.L.O.), Queen's University, Kingston, Canada
| | - Paula D James
- Department of Medicine (K.J.D.-S., J.M., P.D.J., S.L.A., M.L.O.), Queen's University, Kingston, Canada
| | - Donald H Maurice
- Department of Biomedical and Molecular Sciences (A.L.T., L.G.H., L.R.H., M.K.M.W., D.V.C., J.L.M., D.H.M., M.L.O.), Queen's University, Kingston, Canada
| | - Stephen L Archer
- Department of Medicine (K.J.D.-S., J.M., P.D.J., S.L.A., M.L.O.), Queen's University, Kingston, Canada
| | - Mark L Ormiston
- Department of Surgery (M.L.O.), Queen's University, Kingston, Canada
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Evidence of Accumulated Endothelial Progenitor Cells in the Lungs of Rats with Pulmonary Arterial Hypertension by 89Zr-oxine PET Imaging. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2020; 17:1108-1117. [PMID: 32490032 PMCID: PMC7256434 DOI: 10.1016/j.omtm.2020.04.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 04/27/2020] [Indexed: 12/21/2022]
Abstract
Endothelial progenitor cells (EPCs) play a major role in regulating pulmonary vascular remodeling during pulmonary arterial hypertension (PAH) development. Several preclinical and clinical trials of EPCs transplantation have been performed for the treatment of PAH. However, there is no reliable method to monitor real-time cell trafficking and quantify transplanted EPCs. Here in this paper we isolated EPCs from human peripheral blood, identified their functional integrity, and efficiently labeled the EPCs with 89Zr-oxine and DiO. Labeled EPCs were injected into the tail vein of normal and PAH rats to be tracked in vivo. From the microPET/CT images, we found EPCs were distributed primarily in the lung at 1 h and then migrated to the liver and spleen. We could observe the 3,3′ dioctadecyloxacarbocyanine perchlorate (DiO)-labeled EPCs binding in the pulmonary vasculature by CellVizio confocal. The result of quantitative analysis revealed significantly higher accumulation of EPCs in the lungs of PAH rats than in those of healthy rats. The distribution and higher accumulation of EPCs in the lungs of PAH rats could help to evaluate the safety and provide evidence of effectiveness of EPC therapy.
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Cool CD, Kuebler WM, Bogaard HJ, Spiekerkoetter E, Nicolls MR, Voelkel NF. The hallmarks of severe pulmonary arterial hypertension: the cancer hypothesis-ten years later. Am J Physiol Lung Cell Mol Physiol 2020; 318:L1115-L1130. [PMID: 32023082 PMCID: PMC9847334 DOI: 10.1152/ajplung.00476.2019] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 01/31/2020] [Accepted: 01/31/2020] [Indexed: 01/25/2023] Open
Abstract
Severe forms of pulmonary arterial hypertension (PAH) are most frequently the consequence of a lumen-obliterating angiopathy. One pathobiological model is that the initial pulmonary vascular endothelial cell injury and apoptosis is followed by the evolution of phenotypically altered, apoptosis-resistant, proliferating cells and an inflammatory vascular immune response. Although there may be a vasoconstrictive disease component, the increased pulmonary vascular shear stress in established PAH is caused largely by the vascular wall pathology. In this review, we revisit the "quasi-malignancy concept" of severe PAH and examine to what extent the hallmarks of PAH can be compared with the hallmarks of cancer. The cancer model of severe PAH, based on the growth of abnormal vascular and bone marrow-derived cells, may enable the emergence of novel cell-based PAH treatment strategies.
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Affiliation(s)
- Carlyne D Cool
- Department of Pathology, University of Colorado, Anschuetz Campus, Aurora, Colorado
| | - Wolfgang M Kuebler
- Institute of Physiology, Charité - Universitaetsmedizin, Berlin, Germany
| | - Harm Jan Bogaard
- Amsterdam University Medical Centers, Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands
| | - Edda Spiekerkoetter
- Division of Pulmonary and Critical Care Medicine, Stanford University, Palo Alto, California
| | - Mark R Nicolls
- Division of Pulmonary and Critical Care Medicine, Stanford University, Palo Alto, California
| | - Norbert F Voelkel
- Amsterdam University Medical Centers, Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands
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Selvam SN, Bowman M, Inglis M, Kloosterman R, Grabell J, Casey L, Johri AM, James P. Patients with aortic stenosis have von Willebrand factor abnormalities and increased proliferation of endothelial colony forming cells. J Thromb Haemost 2020; 18:593-603. [PMID: 31860769 DOI: 10.1111/jth.14715] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 11/26/2019] [Accepted: 12/13/2019] [Indexed: 01/05/2023]
Abstract
BACKGROUND Patients with aortic stenosis (AS) can experience bleeding complications including gastrointestinal bleeding from angiodysplastic lesions due to acquired von Willebrand syndrome. Studies have pointed to a role for von Willebrand factor (VWF) in angiogenesis. OBJECTIVE The objective of this study was to assess VWF defects in AS patients over time and the impact on angiogenesis using patient-derived endothelial colony-forming cells (ECFCs). PATIENTS/METHODS Plasma sample collection and ECFC isolations were performed before valve replacement surgery, 3 to 5 days after, and 6 months after surgery. Plasma VWF antigen, activity, propeptide, collagen binding, multimers, factor VIII coagulant activity, and ADAMTS13 activity (a disintegrin-like and metalloprotease with thrombospondin type 1 motifs 13) were determined. ECFCs were assessed for VWF and angiopoietin-2 (Ang-2) storage and secretion, cell proliferation, and tubule formation in Matrigel. RESULTS AND CONCLUSIONS Aortic stenosis patients exhibited quantitative and qualitative abnormalities of VWF including significantly increased VWF antigen, activity, and propeptide levels following surgery (P < .01). Increased high molecular weight VWF multimers were observed at all time points and in particular 3 to 5 days after surgery (mean = 14% ± 6%) relative to before (mean = 10% ± 4%), suggesting increased proteolysis by ADAMTS13 pre-operatively in a shear-dependent manner. ECFCs from patients with aortic stenosis were more proliferative than controls (P < .05) and had increased retention of Ang-2 (P < .05) suggesting epigenetic modification of the cells. Overall, there are hemostatic changes in AS patients that are present before valve replacement surgery and these persist long after surgery has occurred. These findings have implications for the current clinical management of AS patients.
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Affiliation(s)
- Soundarya N Selvam
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada
| | - Mackenzie Bowman
- Department of Medicine, Queen's University, Kingston, ON, Canada
| | - Madeline Inglis
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
| | - Robert Kloosterman
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
| | - Julie Grabell
- Department of Medicine, Queen's University, Kingston, ON, Canada
| | - Lara Casey
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada
| | - Amer M Johri
- Department of Medicine, Queen's University, Kingston, ON, Canada
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
| | - Paula James
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada
- Department of Medicine, Queen's University, Kingston, ON, Canada
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Hashimoto R, Lanier GM, Dhagia V, Joshi SR, Jordan A, Waddell I, Tuder R, Stenmark KR, Wolin MS, McMurtry IF, Gupte SA. Pluripotent hematopoietic stem cells augment α-adrenergic receptor-mediated contraction of pulmonary artery and contribute to the pathogenesis of pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2020; 318:L386-L401. [PMID: 31913656 PMCID: PMC7052680 DOI: 10.1152/ajplung.00327.2019] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 12/10/2019] [Accepted: 12/19/2019] [Indexed: 12/13/2022] Open
Abstract
Pulmonary hypertension (PH) is a multicellular and progressive disease with a high mortality rate. Among many cell types, hematopoietic stem cells (HSCs) are incriminated in the pathogenesis of PH. However, our understanding of the mechanisms that increase HSCs in blood and lungs of hypertensive animals or patients and the role played by HSCs in the pathogenesis of PH remains elusive. Studies suggest that glycolysis is critical for the survival and growth of HSCs. In various cell types from hypertensive lungs of animals and patients, glycolysis and the glucose-6-phosphate dehydrogenase (G6PD) activity are increased. Herein, we demonstrated in mice that chronic hypoxia increased HSCs (CD34+, CD117+, CD133+, CD34+/CD117+, and CD34+/CD133+) in bone marrow and blood and around hypertensive pulmonary arteries in a time-dependent manner. Intriguingly, we found fewer CD133+ cells in the bone marrow of C57BL/6 mice compared with Sv129J mice, and C57BL mice developed less severe chronic hypoxia-elicited PH and heart failure than Sv129J mice. Similarly, the numbers of CD34+ and CD117+ cells in blood of patients with pulmonary arterial hypertension (PAH) were higher (>3-fold) compared with healthy individuals. By allogeneic bone marrow transplantation, we found that GFP+ bone marrow cells infiltrated the lungs and accumulated around the pulmonary arteries in lungs of hypoxic mice, and these cells contributed to increased α-adrenergic receptor-mediated contraction of the pulmonary artery cultured in hypoxia. Inhibition of G6PD activity with (3β,5α)-3,21-dihydroxypregnan-20-one, a novel and potent G6PD inhibitor, decreased HSCs in bone marrow, blood, and lungs of hypoxic mice and reduced α-agonist-induced contraction of the pulmonary artery and established hypoxia-induced PH. We did not observe CD133+ cells around the pulmonary arteries in the lungs of chronically hypoxic G6PD-deficient mice. Furthermore, knockdown of G6PD and inhibition of G6PD activity: 1) downregulated canonical and noncanonical Wnt and Fzd receptors genes; 2) upregulated Bmpr1a; 3) decreased Cxcl12, and 4) reduced HSC (CD117+ and CD133+) numbers. In all, our findings demonstrate unexpected function for bone marrow-derived HSCs in augmenting α-adrenergic receptor-mediated contraction of pulmonary arteries and remodeling of pulmonary arteries that contribute to increase pulmonary vascular resistance in PAH patients and hypoxic mice and suggest that G6PD, by regulating expression of genes in the WNT and BMPR signaling, contributed to increase and release of HSCs from the bone marrow in response to hypoxic stimuli.
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Affiliation(s)
- Ryota Hashimoto
- Department of Pharmacology, New York Medical College, Valhalla, New York
| | - Gregg M Lanier
- Department of Cardiology, and Heart and Vascular Institute, Westchester Medical Center and New York Medical College, Valhalla, New York
| | - Vidhi Dhagia
- Department of Pharmacology, New York Medical College, Valhalla, New York
| | - Sachindra R Joshi
- Department of Pharmacology, New York Medical College, Valhalla, New York
| | - Allan Jordan
- Drug Discovery Unit, Cancer Research, UK Manchester Institute, University of Manchester, Manchester, United Kingdom
| | - Ian Waddell
- Drug Discovery Unit, Cancer Research, UK Manchester Institute, University of Manchester, Manchester, United Kingdom
| | - Rubin Tuder
- Department of Pathology, University of Colorado Health Center, Denver, Colorado
| | - Kurt R Stenmark
- Department of Pediatrics, University of Colorado Health Center, Denver, Colorado
| | - Michael S Wolin
- Department of Physiology, New York Medical College, Valhalla, New York
| | - Ivan F McMurtry
- Department of Pharmacology and Medicine, University of South Alabama, Mobile, Alabama
| | - Sachin A Gupte
- Department of Pharmacology, New York Medical College, Valhalla, New York
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Clonally selected primitive endothelial cells promote occlusive pulmonary arteriopathy and severe pulmonary hypertension in rats exposed to chronic hypoxia. Sci Rep 2020; 10:1136. [PMID: 31980720 PMCID: PMC6981224 DOI: 10.1038/s41598-020-58083-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 01/10/2020] [Indexed: 12/15/2022] Open
Abstract
One current concept suggests that unchecked proliferation of clonally selected precursors of endothelial cells (ECs) contribute to severe pulmonary arterial hypertension (PAH). We hypothesized that clonally selected ECs expressing the progenitor marker CD117 promote severe occlusive pulmonary hypertension (PH). The remodelled pulmonary arteries of PAH patients harboured CD117+ ECs. Rat lung CD117+ ECs underwent four generations of clonal expansion to enrich hyperproliferative ECs. The resulting clonally enriched ECs behaved like ECs, as measured by in vitro and in vivo angiogenesis assays. The same primitive ECs showed a limited ability for mesenchymal lineage differentiation. Endothelial differentiation and function were enhanced by blocking TGF-β signalling, promoting bone morphogenic protein (BMP) signalling. The transplantation of the EC clones caused arterio-occlusive PH in rats exposed to chronic hypoxia. These EC clones engrafted in the pulmonary arteries. Yet cessation of chronic hypoxia promoted lung cell apoptosis and resolution of vascular lesions. In conclusion, this is to the best of our knowledge, the first report that clonally enriched primitive ECs promote occlusive pulmonary arteriopathy and severe PH. These primitive EC clones further give rise to cells of endothelial and mesenchymal lineage as directed by BMP and TGF-β signaling.
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