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Balikji J, Mackus M, Garssen J, Hoogbergen MM, Verster JC. Immune Fitness, Migraine, and Headache Complaints in Individuals with Self-Reported Impaired Wound Healing. Int J Gen Med 2023; 16:2245-2253. [PMID: 37293517 PMCID: PMC10246567 DOI: 10.2147/ijgm.s413258] [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] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Accepted: 04/25/2023] [Indexed: 06/10/2023] Open
Abstract
Background Having chronic wounds and impaired wound healing are associated with psychological distress. The current study aims to evaluate migraine and headache complaints in young adults with self-reported impaired wound healing. Methods A survey was conducted among N=1935 young adults (83.6% women), 18-30 years old, living in the Netherlands. Wound healing status was verified, immune fitness was assessed using a single-item rating scale, and ID Migraine was completed. In addition, several questions were answered on past year's headache experiences (including frequency, quantity, type, location, and severity). Results In both the control group (p < 0.001) and the IWH group (p = 0.002) immune fitness was significantly lower among those that reported headaches compared to those that reported no headaches. Individuals with self-reported impaired wound healing (IWH) scored significantly higher on the ID Migraine scale, and individuals of the IWH group scored significantly more often positive for migraine (ie, an ID Migraine score ≥2). They reported a younger age of onset of experiencing headaches, and significantly more often reported having a beating or pounding headache than the control group. Compared to the control group, the IWH group reported being significantly more limited in their daily activities compared to the control group. Conclusion Headaches and migraines are more frequently reported by individuals with self-reported impaired wound healing, and their reported immune fitness is significantly poorer compared to healthy controls. These headache and migraine complaints significantly limit them in their daily activities.
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Affiliation(s)
- Jessica Balikji
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, 3584 CG, the Netherlands
| | - Marlou Mackus
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, 3584 CG, the Netherlands
| | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, 3584 CG, the Netherlands
- Division of Plastic Surgery, Catharina Ziekenhuis, Eindhoven, 5623 EJ, the Netherlands
| | - Maarten M Hoogbergen
- Global Centre of Excellence Immunology, Nutricia Danone Research, Utrecht, 3584 CT, the Netherlands
| | - Joris C Verster
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, 3584 CG, the Netherlands
- Centre for Human Psychopharmacology, Swinburne University, Melbourne, VIC, 3122, Australia
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2
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Erratico S, Belicchi M, Meregalli M, Di Silvestre D, Tripodi L, De Palma A, Jones R, Ferrari E, Porretti L, Trombetta E, Merlo GR, Mauri P, Torrente Y. Effective high-throughput isolation of enriched platelets and circulating pro-angiogenic cells to accelerate skin-wound healing. Cell Mol Life Sci 2022; 79:259. [PMID: 35474498 PMCID: PMC9042989 DOI: 10.1007/s00018-022-04284-4] [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: 01/27/2022] [Revised: 04/01/2022] [Accepted: 04/01/2022] [Indexed: 11/30/2022]
Abstract
Delayed wound healing and chronic skin lesions represent a major health problem. Over the past years, growth factors mediated by platelet-rich plasma (PRP) and cell-based therapies were developed as effective and affordable treatment able to improve wound healing capacity. We have advanced existing concepts to develop a highly efficient high-throughput protocol with proven application for the isolation of PRP and pro-angiogenic cells (AngioPRP). This protocol outlines the effectiveness of AngioPRP in promoting the critical healing process including wound closure, re-epithelialization, granulation tissue growth, and blood vessel regeneration. We coupled this effect with normalization of mechanical properties of rescued mouse wounds, which is sustained by a correct arrangement of elastin and collagen fibers. Proteomic analysis of treated wounds demonstrated a fingerprint of AngioPRP based on the up-regulation of detoxification pathway of glutathione metabolism, correlated to a decrease in inflammatory response. Overall, these results have enabled us to provide a framework for how AngioPRP supports wound healing, opening avenues for further clinical advances.
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Affiliation(s)
| | - Marzia Belicchi
- Unit of Neurology, Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Universitá degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, via Francesco Sforza 35, 20122, Milan, Italy
| | - Mirella Meregalli
- Unit of Neurology, Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Universitá degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, via Francesco Sforza 35, 20122, Milan, Italy
| | - Dario Di Silvestre
- Institute of Technologies in Biomedicine, National Research Council (ITB-CNR), Via Fratelli Cervi, 93, Segrate, 20090, Milan, Italy
| | - Luana Tripodi
- Novystem Spa, viale Piave 21, 20129, Milan, Italy.,Unit of Neurology, Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Universitá degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, via Francesco Sforza 35, 20122, Milan, Italy
| | - Antonella De Palma
- Institute of Technologies in Biomedicine, National Research Council (ITB-CNR), Via Fratelli Cervi, 93, Segrate, 20090, Milan, Italy
| | - Rebecca Jones
- Department of Molecular Biotechnology and Health Science, University of Torino, Via Nizza 52, 10126, Turin, Italy
| | - Emanuele Ferrari
- Institute of Technologies in Biomedicine, National Research Council (ITB-CNR), Via Fratelli Cervi, 93, Segrate, 20090, Milan, Italy
| | - Laura Porretti
- Flow Cytometry Service, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via Francesco Sforza 35, 20122, Milan, Italy
| | - Elena Trombetta
- Flow Cytometry Service, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via Francesco Sforza 35, 20122, Milan, Italy
| | - Giorgio R Merlo
- Department of Molecular Biotechnology and Health Science, University of Torino, Via Nizza 52, 10126, Turin, Italy
| | - Pierluigi Mauri
- Institute of Technologies in Biomedicine, National Research Council (ITB-CNR), Via Fratelli Cervi, 93, Segrate, 20090, Milan, Italy
| | - Yvan Torrente
- Unit of Neurology, Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Universitá degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, via Francesco Sforza 35, 20122, Milan, Italy.
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Cavalcante S, Teixeira M, Duarte A, Ferreira M, Simões MI, Conceição M, Costa M, Ribeiro IP, Gonçalves AC, Oliveira J, Ribeiro F. Endothelial Progenitor Cell Response to Acute Multicomponent Exercise Sessions with Different Durations. BIOLOGY 2022; 11:biology11040572. [PMID: 35453771 PMCID: PMC9025950 DOI: 10.3390/biology11040572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/30/2022] [Accepted: 04/06/2022] [Indexed: 12/04/2022]
Abstract
It is widely accepted that exercise training has beneficial effects on vascular health. Although a dose-dependent relation has been suggested, little is known about the effects of different exercise durations on endothelial markers. This study aimed to assess the effect of single exercise sessions with different durations in the circulating levels of endothelial progenitor cells (EPCs) and endothelial cells (CECs) among adults with cardiovascular risk factors. Ten participants performed two multicomponent exercise sessions, one week apart, lasting 30 and 45 min (main exercise phase). Before and after each exercise session, blood samples were collected to quantify EPCs and CECs by flow cytometry. The change in EPCs was significantly different between sessions by 3.0% (95% CI: 1.3 to 4.7), being increased by 1.8 ± 1.7% (p = 0.009) in the 30 min session vs. −1.2 ± 2.0% (p > 0.05) in the 45 min session. No significant change was observed in CECs [−2.0%, 95%CI: (−4.1 to 0.2)] between the sessions. In conclusion, a multicomponent exercise session of 30 min promotes an acute increase in the circulating levels of EPCs without increasing endothelial damage (measured by the levels of CECs) among adults with cardiovascular risk factors.
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Affiliation(s)
- Suiane Cavalcante
- Research Centre in Physical Activity, Health and Leisure, Faculty of Sport, University of Porto, 4099-002 Porto, Portugal; (S.C.); (J.O.)
| | - Manuel Teixeira
- Institute of Biomedicine—iBiMED, Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal;
| | - Ana Duarte
- Unidade Cuidados na Comunidade Cubo Mágico da Saúde, ACES Baixo Vouga, 3800-120 Aveiro, Portugal; (A.D.); (M.F.); (M.I.S.); (M.C.)
| | - Miriam Ferreira
- Unidade Cuidados na Comunidade Cubo Mágico da Saúde, ACES Baixo Vouga, 3800-120 Aveiro, Portugal; (A.D.); (M.F.); (M.I.S.); (M.C.)
| | - Maria I. Simões
- Unidade Cuidados na Comunidade Cubo Mágico da Saúde, ACES Baixo Vouga, 3800-120 Aveiro, Portugal; (A.D.); (M.F.); (M.I.S.); (M.C.)
| | - Maria Conceição
- Unidade Cuidados na Comunidade Cubo Mágico da Saúde, ACES Baixo Vouga, 3800-120 Aveiro, Portugal; (A.D.); (M.F.); (M.I.S.); (M.C.)
| | - Mariana Costa
- Câmara Municipal de Oliveira do Bairro—Projeto Não Fique Parado, 3800-120 Aveiro, Portugal;
| | - Ilda P. Ribeiro
- Cytogenetics and Genomics Laboratory, Institute of Cellular and Molecular Biology, Faculty of Medicine (FMUC), University of Coimbra, 3004-531 Coimbra, Portugal;
- Institute for Clinical and Biomedical Research (iCBR), Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3004-531 Coimbra, Portugal
| | - Ana Cristina Gonçalves
- Institute for Clinical and Biomedical Research (iCBR)—Group of Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine (FMUC), Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-531 Coimbra, Portugal;
- Laboratory of Oncobiology and Hematology, University Clinic of Hematology, Faculty of Medicine (FMUC), University of Coimbra, 3004-531 Coimbra, Portugal
| | - José Oliveira
- Research Centre in Physical Activity, Health and Leisure, Faculty of Sport, University of Porto, 4099-002 Porto, Portugal; (S.C.); (J.O.)
- Laboratory for Integrative and Translational Research in Population Health (ITR), University of Porto, 4099-002 Porto, Portugal
| | - Fernando Ribeiro
- Institute of Biomedicine—iBiMED, School of Health Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
- Correspondence:
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Zhao H, He Y. The Inhibitory Effect of Lysophosphatidylcholine on Proangiogenesis of Human CD34 + Cells Derived Endothelial Progenitor Cells. Front Mol Biosci 2021; 8:682367. [PMID: 34179086 PMCID: PMC8223510 DOI: 10.3389/fmolb.2021.682367] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 05/28/2021] [Indexed: 12/27/2022] Open
Abstract
Increasing evidence reveals that lysophosphatidylcholine (LPC) is closely related to endothelial dysfunction. The present study aimed to investigate the mechanism of LPC in inhibiting the proangiogenesis and vascular inflammation of human endothelial progenitor cells (EPCs) derived from CD34+ cells. The early EPCs were derived from CD34+ hematopoietic stem cells whose purity was identified using flow cytometry analysis. The surface markers (CD34, KDR, CD31; VE-cadherin, vWF, eNOS) of EPCs were examined by flow cytometry analysis and immunofluorescence. RT-qPCR was used to detect the mRNA expression of inflammatory cytokines (CCL2, IL-8, CCL4) and genes associated with angiogenesis (VEGF, ANG-1, ANG-2) in early EPCs after treatment of LPC (10 μg/ml) or phosphatidylcholine (PC, 10 μg/ml, control). The angiogenesis of human umbilical vein endothelial cells (HUVECs) incubated with the supernatants of early EPCs was detected by a tube formation assay. The mRNA and protein levels of key factors on the PKC pathway (phosphorylated PKC, TGF-β1) were measured by RT-qPCR and western blot. The localization of PKC-β1 in EPCs was determined by immunofluorescence staining. We found that LPC suppressed the expression of CCL2, CCL4, ANG-1, ANG-2, promoted IL-8 expression and had no significant effects on VEGF expression in EPCs. EPCs promoted the angiogenesis of HUVECs, which was significantly inhibited by LPC treatment. Moreover, LPC was demonstrated to promote the activation of the PKC signaling pathway in EPCs. In conclusion, LPC inhibits proangiogenesis of human endothelial progenitor cells derived from CD34+ hematopoietic stem cells.
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Affiliation(s)
- Haijun Zhao
- Department of Pain, The First Hospital of Jilin University, Changchun, China
| | - Yanhui He
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, China
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Leal V, Ribeiro CF, Oliveiros B, António N, Silva S. Intrinsic Vascular Repair by Endothelial Progenitor Cells in Acute Coronary Syndromes: an Update Overview. Stem Cell Rev Rep 2020; 15:35-47. [PMID: 30345477 DOI: 10.1007/s12015-018-9857-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Bone marrow-derived endothelial progenitor cells (EPCs) play a key role in the maintenance of endothelial homeostasis and endothelial repair at areas of vascular damage. The quantification of EPCs in peripheral blood by flow cytometry is a strategy to assess this reparative capacity. The number of circulating EPCs is inversely correlated with the number of cardiovascular risk factors and to the occurrence of cardiovascular events. Therefore, monitoring EPCs levels may provide an accurate assessment of susceptibility to cardiovascular injury, greatly improving risk stratification of patients with high cardiovascular risk, such as those with an acute myocardial infarction. However, there are many issues in the field of EPC identification and quantification that remain unsolved. In fact, there have been conflicting protocols used to the phenotypic identification of EPCs and there is still no consensual immunophenotypical profile that corresponds exactly to EPCs. In this paper we aim to give an overview on EPCs-mediated vascular repair with special focus on acute coronary syndromes and to discuss the different phenotypic profiles that have been used to identify and quantify circulating EPCs in several clinical studies. Finally, we will synthesize evidence on the prognostic role of EPCs in patients with high cardiovascular risk.
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Affiliation(s)
- Vânia Leal
- Group of Pharmacology and Pharmaceutical Care, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal.
| | - Carlos Fontes Ribeiro
- Institute of Pharmacology and Experimental Therapeutics, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Bárbara Oliveiros
- Laboratory of Biostatistics and Medical Informatics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Coimbra, Portugal.,Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Natália António
- Institute of Pharmacology and Experimental Therapeutics, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Cardiology Department, Coimbra Hospital and Universitary Centre, Coimbra, Portugal
| | - Sónia Silva
- Group of Pharmacology and Pharmaceutical Care, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal.,Institute of Pharmacology and Experimental Therapeutics, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
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He M, Cui T, Cai Q, Wang H, Kong H, Xie W. Iptakalim ameliorates hypoxia-impaired human endothelial colony-forming cells proliferation, migration, and angiogenesis via Akt/eNOS pathways. Pulm Circ 2019; 9:2045894019875417. [PMID: 31692706 DOI: 10.1177/2045894019875417] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 08/21/2019] [Indexed: 12/31/2022] Open
Abstract
Hypoxia-associated pulmonary hypertension is characterized by pulmonary vascular remodeling. Pulmonary arterial endothelial cells dysfunction is considered as the initial event. As precursor of endothelial cells, endothelial colony-forming cells (ECFCs) play significant roles in maintenance of endothelium integrity and restoration of normal endothelial cell function. Accumulating data have indicated that hypoxia leads to a decrease in the number and function of ECFCs with defective capacity of endothelial regeneration. Previous studies have reported that the activation of ATP-sensitive potassium channels (KATP) shows therapeutic effects in pulmonary hypertension. However, there have been few reports focusing on the impact of KATP on ECFC function under hypoxic condition. Therefore, the aim of this study was to investigate whether the opening of KATP could regulate hypoxia-induced ECFC dysfunction. Using ECFCs derived from adult peripheral blood, we observed that Iptakalim (Ipt), a novel KATP opener (KCO), significantly promoted ECFC function including cellular viability, proliferation, migration, angiogenesis, and apoptosis compared with ECFCs exposed to hypoxia. Glibenclamide (Gli), a nonselective KATP blocker, could eliminate the effects. The protective role of Ipt is attributed to an increased production of nitric oxide (NO), as well as an enhanced activation of angiogenic transduction pathways, containing Akt and endothelial nitric oxide synthase. Our observations demonstrated that KATP activation could improve ECFC function in hypoxia via Akt/endothelial nitric oxide synthase pathways, which may constitute increase ECFC therapeutic potential for hypoxia-associated pulmonary hypertension treatment.
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Affiliation(s)
- Mengyu He
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ting Cui
- The Inspection Department of the first Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qing Cai
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hong Wang
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hui Kong
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Weiping Xie
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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Brown N, Khan F, Alshaikh B, Berka N, Liacini A, Alawad E, Yusuf K. CD-34 + and VE-cadherin + endothelial progenitor cells in preeclampsia and normotensive pregnancies. Pregnancy Hypertens 2019; 16:42-47. [PMID: 31056159 DOI: 10.1016/j.preghy.2019.02.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 02/12/2019] [Accepted: 02/22/2019] [Indexed: 11/24/2022]
Abstract
OBJECTIVE The objective of our study was to determine levels of endothelial progenitor cells (EPCs) in preeclampsia and normotensive pregnant women. STUDY DESIGN Prospective cohort study of women with preeclampsia and normotensive pregnancies. EPCs were estimated by flow cytometry. Multiple linear regression was used to assess the association of EPCs with preeclampsia adjusting for maternal age, body mass index (BMI), gestation and ethnicity. MAIN OUTCOME MEASURE Levels of EPCs in preeclampsia and normotensive pregnancies, with CD-34 and vascular endothelial (VE)-cadherin as markers of EPCs. VE-cadherin is an endothelial cell adhesion molecule used to delineate endothelial lineage of EPCs. RESULTS There were thirty women in the preeclampsia group and thirty-three in the normotensive group. The two groups were similar except for the BMI and blood pressures, which were higher in preeclampsia. On multiple linear regression, EPCs numbers were significantly higher by 29 (95% confidence interval 11.7-46.6, p = 0.001) in preeclampsia compared to the normotensive group. There was significant positive correlation between EPCs and systolic blood pressure in preeclampsia (Spearman correlation coefficient 0.39, p = 0.03). CONCLUSION Although widely used in cardiovascular disease other than preeclampsia, this is the first study using VE-cadherin as a marker of endothelial lineage to define EPCs in preeclampsia. Our results suggest the higher number of EPCs in preeclampsia may be a response of the bone marrow to endothelial injury.
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Affiliation(s)
- Nicole Brown
- Section of Neonatology, Department of Pediatrics, Cumming School of Medicine, University of Calgary, Alberta, Canada
| | - Faisal Khan
- Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Alberta, Canada
| | - Belal Alshaikh
- Section of Neonatology, Department of Pediatrics, Cumming School of Medicine, University of Calgary, Alberta, Canada
| | - Noureddine Berka
- Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Alberta, Canada
| | - Abdelhamid Liacini
- Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Alberta, Canada
| | - Essa Alawad
- Section of Neonatology, Department of Pediatrics, Cumming School of Medicine, University of Calgary, Alberta, Canada
| | - Kamran Yusuf
- Section of Neonatology, Department of Pediatrics, Cumming School of Medicine, University of Calgary, Alberta, Canada.
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Lian W, Hu X, Pan L, Han S, Cao C, Jia Z, Li M. Human primary CD34 + cells transplantation for critical limb ischemia. J Clin Lab Anal 2018; 32:e22569. [PMID: 29893031 DOI: 10.1002/jcla.22569] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 04/19/2018] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND The goal of this study was to characterize the properties of human CD34+ cells in culture and investigate the feasibility and efficacy of CD34+ transplantation in a mouse model of limb ischemia and in patients with no-option critical limb ischemia. METHODS Human CD34+ cells isolated from peripheral blood and grown in culture for up to four passages stained positively for the surface markers CD34 and CD133 and showed high viability after cryopreservation and recovery. Seven days after surgery to induce limb ischemia, ischemic muscles of nude mice were injected with CD34+ cells. Two weeks later, mice were scored for extent of ischemic injury, and muscle tissue was collected for immunohistochemical analysis of vascular endothelial cells and RT-PCR analysis of cytokine expression. RESULTS Injury scores of CD34+ -treated, but not control, mice were significantly different before and after transplantation. Vascular density and expression of VEGF and bFGF mRNAs were also significantly increased in the treated mice. Patients with severe lower extremity arterial ischemia were injected with their own CD34+ cells in the affected calf, foot, or toe. Significant improvements were observed in peak pain-free walking time, ankle-brachial index, and transcutaneous partial oxygen pressure. These findings demonstrate that growth of human CD34+ cells in vitro and cryopreservations are feasible. CONCLUSION Such cells may provide a renewable source of stem cells for transplantation, which appears to be a feasible, safe, and effective treatment for patients with critical limb ischemia.
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Affiliation(s)
- Weishuai Lian
- Department of interventional and vascular Surgery, Tenth people's Hospital of Tongji University, Shanghai, China
| | - Xiaoxiao Hu
- Department of interventional and vascular Surgery, Tenth people's Hospital of Tongji University, Shanghai, China
| | - Long Pan
- Department of interventional and vascular Surgery, Tenth people's Hospital of Tongji University, Shanghai, China
| | - Shilong Han
- Department of interventional and vascular Surgery, Tenth people's Hospital of Tongji University, Shanghai, China
| | - Chuanwu Cao
- Department of interventional and vascular Surgery, Tenth people's Hospital of Tongji University, Shanghai, China
| | - Zhongzhi Jia
- Department of Interventional Radiology, No. 2 People's Hospital of Changzhou, Nanjing Medical University, Shanghai, China
| | - Maoquan Li
- Department of interventional and vascular Surgery, Tenth people's Hospital of Tongji University, Shanghai, China
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9
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Wang C, Wang Q, Gao W, Zhang Z, Lou Y, Jin H, Chen X, Lei B, Xu H, Mao C. Highly efficient local delivery of endothelial progenitor cells significantly potentiates angiogenesis and full-thickness wound healing. Acta Biomater 2018; 69:156-169. [PMID: 29397318 DOI: 10.1016/j.actbio.2018.01.019] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 12/19/2017] [Accepted: 01/16/2018] [Indexed: 01/01/2023]
Abstract
Wound therapy with a rapid healing performance remains a critical clinical challenge. Cellular delivery is considered to be a promising approach to improve the efficiency of healing, yet problems such as compromised cell viability and functionality arise due to the inefficient delivery. Here, we report the efficient delivery of endothelial progenitor cells (EPCs) with a bioactive nanofibrous scaffold (composed of collagen and polycaprolactone and bioactive glass nanoparticles, CPB) for enhancing wound healing. Under the stimulation of CPB nanofibrous system, the viability and angiogenic ability of EPCs were significantly enhanced through the activation of Hif-1α/VEGF/SDF-1α signaling. In vivo, CPB/EPC constructs significantly enhanced the formation of high-density blood vessels by greatly upregulating the expressions of Hif-1α, VEGF, and SDF-1α. Moreover, owing to the increased local delivery of cells and fast neovascularization within the wound site, cell proliferative activity, granulation tissue formation, and collagen synthesis and deposition were greatly promoted by CPB/EPC constructs resulting in rapid re-epithelialization and regeneration of skin appendages. As a result, the synergistic enhancement of wound healing was observed from CPB/EPC constructs, which suggests the highly efficient delivery of EPCs. CPB/EPC constructs may become highly competitive cell-based therapeutic products for efficient impaired wound healing application. This study may also provide a novel strategy to develop bioactive cell therapy constructs for angiogenesis-related regenerative medicine. STATEMENT OF SIGNIFICANCE This paper reported a highly efficient local delivery of EPCs using bioactive glass-based CPB nanofibrous scaffold for enhancing angiogenesis and wound regeneration. In vitro study showed that CPB can promote the proliferation, migration, and tube formation of EPCs through upregulation of the Hif-1α/VEGF/SDF-1α signaling pathway, indicating that the bioactivity and angiogenic ability of EPCs can be highly maintained and promoted by the CPB scaffold. Moreover, CPB/EPC constructs effectively stimulated the regeneration of diabetic wounds with satisfactory vascularization and better healing outcomes in a full-thickness wound model, suggesting that the highly efficient delivery of EPCs to wound site facilitates angiogenesis and further leads to wound healing. The high angiogenic capacity and excellent healing ability make CPB/EPC constructs highly competitive in cell-based therapeutic products for efficient wound repair application.
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Ding DC, Shyu WC, Lin SZ, Li H. The Role of Endothelial Progenitor Cells in Ischemic Cerebral and Heart Diseases. Cell Transplant 2017; 16:273-84. [PMID: 17503738 DOI: 10.3727/000000007783464777] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Ischemic heart and cerebral diseases are complex clinical syndromes. Endothelial dysfunction caused by dysfunctional endothelial progenitor cells (EPCs) is thought to play a major role in pathophysiology of both types of disease. Healthy EPCs may be able to replace the dysfunctional endothelium through endogenous repair mechanisms. EPC levels are changed in patients with ischemic cerebrovascular and cardiovascular disease and EPCs may play a role in the pathophysiology of these diseases. EPCs are also a marker for preventive and therapeutic interventions. Homing of EPCs to ischemic sites is a mechanism of ischemic tissue repair, and molecules such as stromal-derived factor-1 and integrin may play a role in EPC homing in ischemic disease. Potentiation of the function and numbers of EPCs as well as combining EPCs with other pharmaceutical agents may improve the condition of ischemia patients. However, the precise role of EPCs in ischemic heart and cerebral disease and their therapeutic potential still remain to be explored. Here, we discuss the identification, mobilization, and clinical implications of EPCs in ischemic diseases.
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Affiliation(s)
- Dah-Ching Ding
- Graduate Institute of Medical Science, School of Medicine, Tzu-Chi University, Hualien, Taiwan
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Wu Y, He MY, Ye JK, Ma SY, Huang W, Wei YY, Kong H, Wang H, Zeng XN, Xie WP. Activation of ATP-sensitive potassium channels facilitates the function of human endothelial colony-forming cells via Ca 2+ /Akt/eNOS pathway. J Cell Mol Med 2016; 21:609-620. [PMID: 27709781 PMCID: PMC5323860 DOI: 10.1111/jcmm.13006] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 09/05/2016] [Indexed: 12/17/2022] Open
Abstract
Accumulating data, including those from our laboratory, have shown that the opening of ATP‐sensitive potassium channels (KATP) plays a protective role in pulmonary vascular diseases (PVD). As maintainers of the endothelial framework, endothelial colony‐forming cells (ECFCs) are considered excellent candidates for vascular regeneration in cases of PVD. Although KATP openers (KCOs) have been demonstrated to have beneficial effects on endothelial cells, the impact of KATP on ECFC function remains unclear. Herein, this study investigated whether there is a distribution of KATP in ECFCs and what role KATP play in ECFC modulation. By human ECFCs isolated from adult peripheral blood, KATP were confirmed for the first time to express in ECFCs, comprised subunits of Kir (Kir6.1, Kir6.2) and SUR2b. KCOs such as the classical agent nicorandil (Nico) and the novel agent iptakalim (Ipt) notably improved the function of ECFCs, promoting cell proliferation, migration and angiogenesis, which were abolished by a non‐selective KATP blocker glibenclamide (Gli). To determine the underlying mechanisms, we investigated the impacts of KCOs on CaMKII, Akt and endothelial nitric oxide synthase pathways. Enhanced levels were detected by western blotting, which were abrogated by Gli. This suggested an involvement of Ca2+ signalling in the regulation of ECFCs by KATP. Our findings demonstrated for the first time that there is a distribution of KATP in ECFCs and KATP play a vital role in ECFC function. The present work highlighted a novel profile of KATP as a potential target for ECFC modulation, which may hold the key to the treatment of PVD.
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Affiliation(s)
- Yan Wu
- Department of Respiratory Medicine, WuXi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, China
| | - Meng-Yu He
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jian-Kui Ye
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shu-Ying Ma
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wen Huang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yong-Yue Wei
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hui Kong
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hong Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiao-Ning Zeng
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wei-Ping Xie
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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12
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Hwang I, Lee HS, Yu HS, Kim ME, Lee JS, Park K. Testosterone modulates endothelial progenitor cells in rat corpus cavernosum. BJU Int 2016; 117:976-81. [DOI: 10.1111/bju.13438] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Affiliation(s)
- Insang Hwang
- Department of Urology; Chonnam National University Medical School; Sexual Medicine Research Center; Chonnam National University; Gwangju Korea
| | - Hyun-Suk Lee
- Department of Urology; Chonnam National University Medical School; Sexual Medicine Research Center; Chonnam National University; Gwangju Korea
| | - Ho Song Yu
- Department of Urology; Chonnam National University Medical School; Sexual Medicine Research Center; Chonnam National University; Gwangju Korea
| | - Mi Eun Kim
- Department of Biology; BK21-plus Research Team for Bioactive Control Technology; College of Natural Sciences; Chosun University; Gwangju Korea
| | - Jun Sik Lee
- Department of Biology; BK21-plus Research Team for Bioactive Control Technology; College of Natural Sciences; Chosun University; Gwangju Korea
| | - Kwangsung Park
- Department of Urology; Chonnam National University Medical School; Sexual Medicine Research Center; Chonnam National University; Gwangju Korea
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13
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Suen CM, Mei SHJ, Kugathasan L, Stewart DJ. Targeted delivery of genes to endothelial cells and cell- and gene-based therapy in pulmonary vascular diseases. Compr Physiol 2014; 3:1749-79. [PMID: 24265244 DOI: 10.1002/cphy.c120034] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Pulmonary arterial hypertension (PAH) is a devastating disease that, despite significant advances in medical therapies over the last several decades, continues to have an extremely poor prognosis. Gene therapy is a method to deliver therapeutic genes to replace defective or mutant genes or supplement existing cellular processes to modify disease. Over the last few decades, several viral and nonviral methods of gene therapy have been developed for preclinical PAH studies with varying degrees of efficacy. However, these gene delivery methods face challenges of immunogenicity, low transduction rates, and nonspecific targeting which have limited their translation to clinical studies. More recently, the emergence of regenerative approaches using stem and progenitor cells such as endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs) have offered a new approach to gene therapy. Cell-based gene therapy is an approach that augments the therapeutic potential of EPCs and MSCs and may deliver on the promise of reversal of established PAH. These new regenerative approaches have shown tremendous potential in preclinical studies; however, large, rigorously designed clinical studies will be necessary to evaluate clinical efficacy and safety.
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Affiliation(s)
- Colin M Suen
- Sprott Centre for Stem Cell Research, The Ottawa Hospital Research Institute and University of Ottawa, Ottawa, Ontario, Canada
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Krüger K, Pilat C, Schild M, Lindner N, Frech T, Muders K, Mooren FC. Progenitor cell mobilization after exercise is related to systemic levels of G-CSF and muscle damage. Scand J Med Sci Sports 2014; 25:e283-91. [PMID: 25264280 DOI: 10.1111/sms.12320] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/10/2014] [Indexed: 01/05/2023]
Abstract
Different types of exercise are characterized by the ability to induce specific physiological stimuli that might be able to induce the mobilization of progenitor cells. The aim of the current study was to investigate the mobilization of hematopoietic progenitor cells (HPCs) and endothelial progenitor cells (EPCs) in response to endurance, resistance, and eccentric endurance exercise and their relation to markers of muscle damage and inflammation. Healthy male subjects performed acute bouts of either endurance exercise, resistance exercise, or eccentric endurance exercise. Numbers of progenitor cells and several markers of muscle damage and inflammation were determined. Although the endurance exercise was followed by an immediate and short increase of both HPCs and EPCs, the eccentric exercise evoked a long lasting increase up to 24 h for HPCs and 48 h for EPCs (P < 0.05). After resistance exercise, an increase of HPCs was only found 3 h after exercise (P < 0.05). A correlation was found between mobilized progenitor cells and systemic levels of granulocyte colony-stimulating factor (G-CSF) levels (r = 0.54 and r = 0.51, P < 0.05) as well as for HPCs and creatine kinase levels (r = 0.57, P < 0.05). These results suggest that mobilization of progenitor cells is related to the type of exercise and possibly mediated by G-CSF and muscle damage.
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Affiliation(s)
- K Krüger
- Department of Sports Medicine, Institute of Sports Sciences, Justus-Liebig-University, Giessen, Germany
| | - C Pilat
- Department of Sports Medicine, Institute of Sports Sciences, Justus-Liebig-University, Giessen, Germany
| | - M Schild
- Department of Sports Medicine, Institute of Sports Sciences, Justus-Liebig-University, Giessen, Germany
| | - N Lindner
- Department of Sports Medicine, Institute of Sports Sciences, Justus-Liebig-University, Giessen, Germany
| | - T Frech
- Department of Sports Medicine, Institute of Sports Sciences, Justus-Liebig-University, Giessen, Germany
| | - K Muders
- Department of Sports Medicine, Institute of Sports Sciences, Justus-Liebig-University, Giessen, Germany
| | - F C Mooren
- Department of Sports Medicine, Institute of Sports Sciences, Justus-Liebig-University, Giessen, Germany
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15
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McLoughlin P, Keane MP. Physiological and pathological angiogenesis in the adult pulmonary circulation. Compr Physiol 2013; 1:1473-508. [PMID: 23733650 DOI: 10.1002/cphy.c100034] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Angiogenesis occurs during growth and physiological adaptation in many systemic organs, for example, exercise-induced skeletal and cardiac muscle hypertrophy, ovulation, and tissue repair. Disordered angiogenesis contributes to chronic inflammatory disease processes and to tumor growth and metastasis. Although it was previously thought that the adult pulmonary circulation was incapable of supporting new vessel growth, over that past 10 years new data have shown that angiogenesis within this circulation occurs both during physiological adaptive processes and as part of the pathogenic mechanisms of lung diseases. Here we review the expression of vascular growth factors in the adult lung, their essential role in pulmonary vascular homeostasis and the changes in their expression that occur in response to physiological challenges and in disease. We consider the evidence for adaptive neovascularization in the pulmonary circulation in response to alveolar hypoxia and during lung growth following pneumonectomy in the adult lung. In addition, we review the role of disordered angiogenesis in specific lung diseases including idiopathic pulmonary fibrosis, acute adult distress syndrome and both primary and metastatic tumors of the lung. Finally, we examine recent experimental data showing that therapeutic enhancement of pulmonary angiogenesis has the potential to treat lung diseases characterized by vessel loss.
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Affiliation(s)
- Paul McLoughlin
- University College Dublin, School of Medicine and Medical Sciences, Conway Institute, and St. Vincent's University Hospital, Dublin, Ireland.
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16
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Traish AM, Galoosian A. Androgens modulate endothelial function and endothelial progenitor cells in erectile physiology. Korean J Urol 2013; 54:721-31. [PMID: 24255752 PMCID: PMC3830963 DOI: 10.4111/kju.2013.54.11.721] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Accepted: 09/24/2013] [Indexed: 12/21/2022] Open
Abstract
The incidence of erectile dysfunction (ED) increases with age and cardiovascular disease risk factors, such as hypertension, hyperlipidemia, insulin resistance, obesity, and diabetes. These risk factors are thought to contribute to endothelial dysfunction and atherosclerosis, thus contributing to the pathophysiology of ED. The role of the endothelium in regulating erectile physiology is well established. However, the role of androgens in modulating endothelial function and endothelial repair mechanisms subsequent to vascular injury in erectile tissue remains a subject of intensive research. The clinical and preclinical evidence discussed in this review suggests that androgens regulate endothelial function and also play an important role in the development and maturation of endothelial progenitor cells (EPCs), which are thought to play a critical role in repair of endothelial injury in vascular beds. In this review, we discuss the data available on the effects of androgens on endothelial function and EPCs in the repair of vascular injury. Indeed, more research is needed to fully understand the molecular and cellular basis of androgen action in regulating the development, differentiation, maturation, migration, and homing of EPCs to the site of injury. A better understanding of these processes will be critical to the development of new therapeutic approaches to the treatment of vascular ED.
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Affiliation(s)
- Abdulmaged M Traish
- Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA. ; Department of Urology, Boston University School of Medicine, Boston, MA, USA
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17
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Effect of conversion from ciclosporin to tacrolimus on endothelial progenitor cells in stable long-term kidney transplant recipients. Transplantation 2013; 95:1338-45. [PMID: 23594858 DOI: 10.1097/tp.0b013e31828fabb3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Endothelial progenitor cell (EPC) counts are proposed surrogate markers for vascular function and cardiovascular risk. The effect of tacrolimus (TAC) on EPC is unknown. METHODS In this randomized controlled trial, we assigned 148 stable long-term kidney transplant recipients (KTR) to maintaining ciclosporin (CSA) or to commencing TAC-based immunosuppression at a 2:1 ratio. EPC counts (CD34/KDR) after 24 months were defined as primary endpoint. RESULTS The intent-to-treat analysis included 141 KTR (estimated glomerular filtration rate, 46.7 [40.1-61.8] mL/min per 1.73 m). Median (interquartile range [IQR]) EPC counts at baseline and month 24 were 6 (2-9) and 3 (1-9) cells and 4 (2-8) and 2 (0-5) cells per 5×10 mononuclear cells in CSA and TAC, respectively. Median (IQR) circulating angiogenic cells at baseline and month 24 were 28 (10.7-57) and 44.33 (14.6-59.8) cells and 22 (10.8-41) and 21 (9.7-49.5) cells per high-power field in CSA and TAC, respectively. Median (IQR) endothelial cell colony-forming units count per well at baseline and month 24 were 10.5 (3.3-34.3) and 4.38 (1.7-26.5) in CSA and significantly declined from 9.31 (1.8-29.3) to 4.13 (1.1-9.5) in TAC (P=0.003). There were no cardiovascular events in either group. CONCLUSION Although late conversion from CSA to TAC appears safe in KTR, conversion to TAC has no favorable effect on EPC. Low EPC levels are associated with a higher risk of subsequent cardiovascular events and are therefore of prognostic value. Their trend to decline over time deserves further examination.
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18
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Kasim S, Moran D, McFadden E. Vulnerable plaque: from bench to bedside; local pacification versus systemic therapy. Heart Views 2013; 13:139-45. [PMID: 23439781 PMCID: PMC3573359 DOI: 10.4103/1995-705x.105731] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Critical coronary stenoses accounts for a small proportion of acute coronary syndromes and sudden death. The majority are caused by coronary thromboses that arise from a nonangiographically obstructive atheroma. Recent developments in noninvasive imaging of so-called vulnerable plaques created opportunities to direct treatment to prevent morbidity and mortality associated with these high-risk lesions. This review covers therapy employed in the past, present, and potentially in the future as the natural history of plaque assessment unfolds.
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Affiliation(s)
- Sazzli Kasim
- Cardiology Unit, Medical Faculty, UiTM Sg Buloh, Selangor, Malaysia ; Division of Cardiology, Cork University Hospital, Cork, Ireland
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19
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20
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Koutroumpi M, Dimopoulos S, Psarra K, Kyprianou T, Nanas S. Circulating endothelial and progenitor cells: Evidence from acute and long-term exercise effects. World J Cardiol 2012; 4:312-326. [PMID: 23272272 PMCID: PMC3530787 DOI: 10.4330/wjc.v4.i12.312] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2012] [Revised: 10/31/2012] [Accepted: 11/06/2012] [Indexed: 02/06/2023] Open
Abstract
Circulating bone-marrow-derived cells, named endothelial progenitor cells (EPCs), are capable of maintaining, generating, and replacing terminally differentiated cells within their own specific tissue as a consequence of physiological cell turnover or tissue damage due to injury. Endothelium maintenance and restoration of normal endothelial cell function is guaranteed by a complex physiological procedure in which EPCs play a significant role. Decreased number of peripheral blood EPCs has been associated with endothelial dysfunction and high cardiovascular risk. In this review, we initially report current knowledge with regard to the role of EPCs in healthy subjects and the clinical value of EPCs in different disease populations such as arterial hypertension, obstructive sleep-apnea syndrome, obesity, diabetes mellitus, peripheral arterial disease, coronary artery disease, pulmonary hypertension, and heart failure. Recent studies have introduced the novel concept that physical activity, either performed as a single exercise session or performed as part of an exercise training program, results in a significant increase of circulating EPCs. In the second part of this review we provide preliminary evidence from recent studies investigating the effects of acute and long-term exercise in healthy subjects and athletes as well as in disease populations.
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Affiliation(s)
- Matina Koutroumpi
- Matina Koutroumpi, Stavros Dimopoulos, Serafim Nanas, Cardiopulmonary Exercise Testing and Rehabilitation Laboratory, 1st Critical Care Medicine Department, Evangelismos Hospital, National and Kapodistrian University of Athens, 10676 Athens, Greece
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21
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Systemic human Netrin-1 gene delivery by adeno-associated virus type 8 alters leukocyte accumulation and atherogenesis in vivo. Gene Ther 2010; 18:437-44. [PMID: 21160531 DOI: 10.1038/gt.2010.155] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Atherosclerosis is an inflammatory disorder of arteries. Atherosclerotic plaque, in its early to intermediate stages, is composed largely of lipid-engorged foam cells. These foam cells are derived from the trafficking of monocytes (Mo) into the arterial intima, attracted to the site by chemoattractants. Given that foam cells are derived from the trafficking of Mo, the use of Netrin-1, an Mo chemorepellent, may be useful in limiting Mo accumulation and subsequent plaque formation. To investigate the potential of Netrin-1 for limiting atherosclerosis, we systemically delivered its human (h) cDNA by adeno-associated virus type 8 (AAV8, single-stranded structure) delivery into low-density lipoprotein receptor knockout (LDLR-/-) mice and placed the animals on a high cholesterol diet (HCD). Compared with control neomycin resistance (Neo) gene delivery/HCD, hNetrin-1 delivery resulted in a significant reduction in plaque formation, as determined by larger aortic lumen size, thinner intima-media thickness and lower blood velocity than the Neo/HCD control (all statistically significant). Indices of monocyte/macrophage (Mo/MΦ) accumulation, CD68, integrin, alpha M (ITGAM) and egf-like module containing, mucin-like, hormone receptor-like 1 (EMR-1), were reduced in hNetrin-1/HCD-treated animal's aortas and spleens compared with Neo/HCD-treated animals. Unexpectedly, CD25 and foxp3 (regulatory T cells (Tregs)) in the aorta were strongly upregulated. This is the first time the Mo/MΦ chemorepellent approach, and specific Netrin-1 gene delivery, has been performed for the reduction of Mo/MΦ burden and atherosclerosis. In addition, Netrin-1 has never before been linked to altered Treg levels. These data strongly suggest that hNetrin-1 gene delivery can reduce Mo/MΦ accumulation, inflammation and subsequent plaque formation.
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22
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Thacker SG, Berthier CC, Mattinzoli D, Rastaldi MP, Kretzler M, Kaplan MJ. The detrimental effects of IFN-α on vasculogenesis in lupus are mediated by repression of IL-1 pathways: potential role in atherogenesis and renal vascular rarefaction. THE JOURNAL OF IMMUNOLOGY 2010; 185:4457-69. [PMID: 20805419 DOI: 10.4049/jimmunol.1001782] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Systemic lupus erythematosus (SLE) is characterized by increased vascular risk due to premature atherosclerosis independent of traditional risk factors. We previously proposed that IFN-α plays a crucial role in premature vascular damage in SLE. IFN-α alters the balance between endothelial cell apoptosis and vascular repair mediated by endothelial progenitor cells (EPCs) and myeloid circulating angiogenic cells (CACs). In this study, we demonstrate that IFN-α promotes an antiangiogenic signature in SLE and control EPCs/CACs, characterized by transcriptional repression of IL-1α and β, IL-1R1, and vascular endothelial growth factor A, and upregulation of IL-1R antagonist and the decoy receptor IL-1R2. IL-1β promotes significant improvement in the functional capacity of lupus EPCs/CACs, therefore abrogating the deleterious effects of IFN-α. The beneficial effects from IL-1 are mediated, at least in part, by increases in EPC/CAC proliferation, by decreases in EPC/CAC apoptosis, and by preventing the skewing of CACs toward nonangiogenic pathways. IFN-α induces STAT2 and 6 phosphorylation in EPCs/CACs, and JAK inhibition abrogates the transcriptional antiangiogenic changes induced by IFN-α in these cells. Immunohistochemistry of renal biopsies from patients with lupus nephritis, but not anti-neutrophil cytoplasmic Ab-positive vasculitis, showed this pathway to be operational in vivo, with increased IL-1R antagonist, downregulation of vascular endothelial growth factor A, and glomerular and blood vessel decreased capillary density, compared with controls. Our study introduces a novel putative pathway by which type I IFNs may interfere with vascular repair in SLE through repression of IL-1-dependent pathways. This could promote atherosclerosis and loss of renal function in this disease.
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Affiliation(s)
- Seth G Thacker
- Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA
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Shimizu K, Sato M, Zhang Y, Kouguchi T, Takahata Y, Morimatsu F, Shimizu M. The bioavailable octapeptide Gly-Ala-Hyp-Gly-Leu-Hyp-Gly-Pro stimulates nitric oxide synthesis in vascular endothelial cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2010; 58:6960-6965. [PMID: 20459131 DOI: 10.1021/jf100388w] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2023]
Abstract
Gly-Ala-Hyp-Gly-Leu-Hyp-Gly-Pro (GAXGLXGP, X: Hyp), an octapeptide contained in chicken collagen hydrolysate, inhibits angiotensin I-converting enzyme activity in vitro. Intestinal Caco-2 and bovine aortic endothelial cells (BAECs) were used to investigate whether the transported GAXGLXGP improves vascular function. When GAXGLXGP was added to the apical side of Caco-2 monolayers, the intact form of GAXGLXGP was released to the basolateral side without incorporation into the cells. This transport was energy-independent but was associated with tight junction permeability. GAXGLXGP was then added to BAECs, and endothelial nitric oxide (NO) synthase (eNOS) activation was examined. GAXGLXGP at a concentration of 10 microM stimulated production of NO during a 1 h incubation. This event involved phosphorylation of eNOS at Ser(1179) without a change in the total eNOS protein level. These findings indicate that GAXGLXGP absorbed intact through the intestinal epithelium has direct effects on eNOS activity in vascular endothelial cells, leading to NO synthesis, thereby suggesting the potential for improvement in vascular function.
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Affiliation(s)
- Kazuo Shimizu
- R&D Center, Nippon Meat Packers Inc, Tsukuba, Ibaraki 300-2646, Japan.
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Transplantation of endothelial progenitor cells alleviates renal interstitial fibrosis in a mouse model of unilateral ureteral obstruction. Life Sci 2010; 86:798-807. [DOI: 10.1016/j.lfs.2010.03.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2009] [Revised: 03/10/2010] [Accepted: 03/10/2010] [Indexed: 10/19/2022]
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25
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Mahendra J, Mahendra L, Kurian VM, Jaishankar K, Mythilli R. Prevalence of periodontal pathogens in coronary atherosclerotic plaque of patients undergoing coronary artery bypass graft surgery. J Maxillofac Oral Surg 2009; 8:108-13. [PMID: 23139486 DOI: 10.1007/s12663-009-0028-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2009] [Accepted: 06/12/2009] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Chronic bacterial infections have been associated with an increased risk for atherosclerosis and coronary artery disease. The ability of oral pathogens to colonize in coronary atheromatous plaque is well known. The aim of our study was to detect the presence of four common periodontal pathogens in coronary plaques. We detected the presence of 16S rRNA of Treponema denticola, Eikenella Corrodens, Porphyromonas gingivalis and Campylobacter rectus in subgingival and atherosclerotic plaques of CABG surgery by using Polymerase Chain Reaction. METHODS 51 patients in the age group of 40 to 80 years with chronic periodontitis were recruited for the study. These patients were suffering from Coronary Artery Disease (CAD) and underwent Coronary Artery Bypass Grafting (CABG). DNA was extracted from the subgingival plaque and coronary atheromatous plaque samples. Universal Primer for the general detection of bacterial DNA and the primers for T.denticola, E. Corrodens, C.rectus and P.gingivalis were used to amplify part of 16SrRNA gene by Polymerase Chain Reaction. RESULTS T.denticola, E.corrodens, C.rectus and P.gingivalis were detected in 49.01 %, 27.45 %, 21.51% and 45.10% of atherosclerotic plaque samples. In both subgingival and coronary plaque samples, T. denticola was detected in 39.21% of the cases, E.corrodens in 19.60%, C.rectus in 11.76% and P.gingivalis in 39.22% of the cases respectively. CONCLUSION Our study revealed the presence of significant bacterial DNA of oral pathogens in coronary plaques. This suggests possible relationship between periodontal infection and atherosclerosis and can help devise preventive treatment strategies.
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Affiliation(s)
- Jaideep Mahendra
- Dept. of Periodontics, Meenakshi Ammal Dental College, Chennai, India ; Dept. of Periodontics, Meenakshi Ammal Dental College, Maduravoil, Chennai, India
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Moreno PR, Sanz J, Fuster V. Promoting mechanisms of vascular health: circulating progenitor cells, angiogenesis, and reverse cholesterol transport. J Am Coll Cardiol 2009; 53:2315-23. [PMID: 19539140 DOI: 10.1016/j.jacc.2009.02.057] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2008] [Revised: 01/27/2009] [Accepted: 02/06/2009] [Indexed: 12/20/2022]
Abstract
To understand and promote vascular health, we must reduce the aggression to the vessel wall and enhance the physiologic mechanisms leading to restoration of vessel wall function. Three main defense mechanisms are responsible for maintaining cardiovascular homeostasis: the regenerative production of endothelial progenitor cells, vessel wall angiogenesis, and macrophage-mediated reverse cholesterol transport. Endothelial progenitor cells can restore vessel wall function and reduce atherosclerosis. In patients with risk factors, high levels of circulating progenitor cells increase event-free survival from cardiovascular events. Mobilization of progenitor cells includes physical and pharmacological approaches, of which exercise and statin therapy have great potential. Angiogenesis is a pivotal defense mechanism to counteract hypoxia and is needed for plaque regression. However, neovessels are susceptible for intraplaque hemorrhage, particularly in diabetes mellitus. In these patients, the haptoglobin 2-2 genotype is the more affected, and may benefit from an antioxidant approach. Finally, the reverse cholesterol transport system is the main mechanism for plaque regression. In addition to high-density lipoprotein cholesterol, apolipoprotein A-I therapies and the promotion of cholesterol efflux from macrophages by the ABCA1 and ABCG1 transporter systems hold great promise and may be available for therapeutic application in the near future.
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Affiliation(s)
- Pedro R Moreno
- Zena and Michael A. Wiener Cardiovascular Institute, Marie-Josee and Henry R. Kravis Cardiovascular Health Center, The Mount Sinai School of Medicine, New York, New York 10029, USA
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27
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Antihypertensive effects and endothelial progenitor cell activation by intake of chicken collagen hydrolysate in pre- and mild-hypertension. Biosci Biotechnol Biochem 2009; 73:422-4. [PMID: 19202283 DOI: 10.1271/bbb.80189] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Chicken collagen hydrolysate was given to 15 mildly hypertensive subjects for 4 weeks. Blood pressure was significantly decreased by 11.8 mmHg (P<0.01). A reduction in plasma renin activity was observed in blood test after intake. A colony assay of endothelial progenitor cells in blood samples from non-smokers revealed an approximately 30% increase in the number of colonies.
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Fan E, Zhang L, Jiang S, Bai Y. Beneficial effects of resveratrol on atherosclerosis. J Med Food 2009; 11:610-4. [PMID: 19053850 DOI: 10.1089/jmf.2007.0091] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Atherosclerosis, a progressive disease characterized by the accumulation of lipids and fibrous elements in the arteries, is a most important contributor to cardiovascular diseases. Resveratrol is a naturally occurring phytopolyphenol compound and shows the ability to reduce the risk of cardiovascular diseases. In this review, beneficial effects of resveratrol on the initiation and progression of atherosclerosis, including regulation of vasodilator and vasoconstrictor production, inhibition of oxidative stress/reactive oxygen species generation, anti-inflammation, inhibition of modification of low-density lipoproteins, anti-platelet aggregation, and its abilities to impede progression and modulate complications of atherosclerosis, are discussed.
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Affiliation(s)
- Enguo Fan
- College of Life Sciences, Nankai University, Tian Jin, People's Republic of China.
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Sozer S, Wang X, Zhang W, Fiel MI, Ishii T, Wang J, Wisch N, Xu M, Hoffman R. Circulating angiogenic monocyte progenitor cells are reduced in JAK2V617F high allele burden myeloproliferative disorders. Blood Cells Mol Dis 2008; 41:284-91. [DOI: 10.1016/j.bcmd.2008.06.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2008] [Accepted: 06/27/2008] [Indexed: 02/02/2023]
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Normal levels and function of endothelial progenitor cells in patients with psoriatic arthritis. Rheumatol Int 2008; 29:257-62. [PMID: 18704428 DOI: 10.1007/s00296-008-0676-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2008] [Accepted: 08/01/2008] [Indexed: 10/21/2022]
Abstract
Endothelial progenitor cells (EPCs) are a population of bone marrow derived cells which have been attributed with the ability to migrate into areas of tissue ischemia and to posses reparative qualities. EPCs have been shown to be decreased in level and function in various inflammatory disorders. Psoriasis and psoriatic arthritis are associated with an increase in cardiovascular morbidity. The aim of the study was to investigate the number of EPCs among patients suffering from psoriasis and psoriatic arthritis. Patients suffering from active psoriasis and psoriatic arthritis were recruited as well as healthy controls. Disease activity was assessed with the DAS-28, BASDAI and PASI scores. Peripheral blood mononuclear cells were isolated and EPC numbers evaluated by FACS analysis using the CD34/133 and CD34/KDR. No significant difference was found between numbers of EPCs between healthy controls, patients with psoriasis and psoriatic arthritis. A significant correlation was found between levels of VGEF and the BASDAI score. The results of the current study do not support a significant role for EPCs in the pathogenesis of psoriasis and psoriatic arthritis.
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31
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Coppolino G, Campo S, Bolignano D, Sturiale A, Giacobbe MS, Loddo S, Buemi M. Effect of immunoglobulin treatment on endothelial progenitor cells in systemic lupus erythematosus. Ann Rheum Dis 2008; 67:1047-8. [PMID: 18556444 DOI: 10.1136/ard.2007.081562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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Coppolino G, Bolignano D, Campo S, Loddo S, Teti D, Buemi M. Circulating Progenitor Cells after Cold Pressor Test in Hypertensive and Uremic Patients. Hypertens Res 2008; 31:717-24. [DOI: 10.1291/hypres.31.717] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Chen MC, Chen CJ, Yang CH, Liu WH, Fang CY, Hsieh YK, Chang HW. Relationship of the percentage of circulating endothelial progenitor cell to the severity of coronary artery disease. Heart Vessels 2008; 23:47-52. [PMID: 18273546 DOI: 10.1007/s00380-007-1006-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2006] [Accepted: 07/20/2007] [Indexed: 10/22/2022]
Abstract
Previous study demonstrated that the percentage of circulating endothelial progenitor cells was reduced in patients with coronary artery disease. However, the relationship of the percentage of circulating endothelial progenitor cells to the severity of coronary artery disease has not been investigated. The percentages of circulating endothelial progenitor cells were measured in 78 consecutive patients with unstable angina, as well as in 32 healthy volunteers. Dual-stained cells expressing CD34 and vascular endothelial growth factor receptor-2 were judged to be endothelial progenitor cells and were analyzed using flow cytometry. On stepwise multiple linear regression analysis, the percentages of circulating endothelial progenitor cells were independently decreased in patients with unstable coronary artery disease compared with those in the healthy volunteers (P < 0.05). Among patients with unstable coronary artery disease, the percentage of patients with at least one occluded vessel was significantly higher in patients with multi-vessel disease than in patients with single-vessel disease (P < 0.04). On stepwise multiple linear regression analysis, the percentages of circulating endothelial progenitor cells were independently decreased in patients with multi-vessel coronary artery disease compared with those in patients with single-vessel coronary artery disease (P < 0.03). Among patients with unstable coronary artery disease, the percentage of circulating endothelial progenitor cells was significantly related to the severity of coronary artery disease.
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Affiliation(s)
- Mien-Cheng Chen
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Hsiang, Kaohsiung Hsien 83301, Taiwan.
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Li Z, Suzuki Y, Huang M, Cao F, Xie X, Connolly AJ, Yang PC, Wu JC. Comparison of reporter gene and iron particle labeling for tracking fate of human embryonic stem cells and differentiated endothelial cells in living subjects. Stem Cells 2008; 26:864-73. [PMID: 18218820 DOI: 10.1634/stemcells.2007-0843] [Citation(s) in RCA: 164] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Human embryonic stem (hES) cells are pluripotent stem cells capable of self-renewal and differentiation into virtually all cell types. Thus, they hold tremendous potential as cell sources for regenerative therapies. The concurrent development of accurate, sensitive, and noninvasive technologies capable of monitoring hES cells engraftment in vivo can greatly expedite basic research prior to future clinical translation. In this study, hES cells were stably transduced with a lentiviral vector carrying a novel double-fusion reporter gene that consists of firefly luciferase and enhanced green fluorescence protein. Reporter gene expression had no adverse effects on cell viability, proliferation, or differentiation to endothelial cells (human embryonic stem cell-derived endothelial cells [hESC-ECs]). To compare the two popular imaging modalities, hES cells and hESC-ECs were then colabeled with superparamagnetic iron oxide particles before transplantation into murine hind limbs. Longitudinal magnetic resonance (MR) imaging showed persistent MR signals in both cell populations that lasted up to 4 weeks. By contrast, bioluminescence imaging indicated divergent signal patterns for hES cells and hESC-ECs. In particular, hESC-ECs showed significant bioluminescence signals at day 2, which decreased progressively over the following 4 weeks, whereas bioluminescence signals from undifferentiated hES cells increased dramatically during the same period. Post-mortem histology and immunohistochemistry confirmed teratoma formation after injection of undifferentiated hES cells but not hESC-ECs. From these data taken together, we concluded that reporter gene is a better marker for monitoring cell viability, whereas iron particle labeling is a better marker for high-resolution detection of cell location by MR. Furthermore, transplantation of predifferentiated rather than undifferentiated hES cells would be more suited for avoiding teratoma formation.
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Affiliation(s)
- Zongjin Li
- Department of Radiology and Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, California 94305-5344, USA
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de la Peña M, Barceló A, Barbe F, Piérola J, Pons J, Rimbau E, Ayllón O, Agustí AGN. Endothelial function and circulating endothelial progenitor cells in patients with sleep apnea syndrome. ACTA ACUST UNITED AC 2007; 76:28-32. [PMID: 17921670 DOI: 10.1159/000109643] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2007] [Accepted: 06/16/2007] [Indexed: 12/22/2022]
Abstract
BACKGROUND Endothelial dysfunction and cardiovascular diseases are frequent in patients with obstructive sleep apnea (OSA). Circulating endothelial progenitor cells (EPCs) contribute to repair dysfunctional endothelium and have been related to increased cardiovascular risk. OBJECTIVES We tested the hypothesis that the number of circulating EPCs may be altered in OSA patients. METHODS EPCs (CD34+ VEGF-R2+) were isolated and quantified from peripheral blood samples of OSA patients (n = 13) and healthy controls (n = 13) matched for age and sex. All subjects were free of any other known cardiovascular risk factors. The plasma levels of vascular endothelial growth factor (VEGF) were also determined, and the endothelium-dependent and endothelium-independent vascular function was assessed in all subjects. RESULTS Patients with OSA had lower levels of EPCs (p < 0.05) and higher plasma levels of VEGF (p < 0.05) than controls. Endothelial function was not different between OSA and controls. CONCLUSIONS Patients with OSA free of any other known cardiovascular risk factor show a reduced number of circulating EPCs and an increase in plasma VEGF levels. These alterations may contribute to future endothelial dysfunction in these patients.
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Affiliation(s)
- Mónica de la Peña
- Servei de Pneumología, Hospital Universitari Son Dureta, Palma de Mallorca, España.
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Cipriani P, Guiducci S, Miniati I, Cinelli M, Urbani S, Marrelli A, Dolo V, Pavan A, Saccardi R, Tyndall A, Giacomelli R, Cerinic MM. Impairment of endothelial cell differentiation from bone marrow-derived mesenchymal stem cells: new insight into the pathogenesis of systemic sclerosis. ACTA ACUST UNITED AC 2007; 56:1994-2004. [PMID: 17530639 DOI: 10.1002/art.22698] [Citation(s) in RCA: 110] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
OBJECTIVE Systemic sclerosis (SSc) is a disorder characterized by vascular damage and fibrosis of the skin and internal organs. Despite marked tissue hypoxia, there is no evidence of compensatory angiogenesis. The ability of mesenchymal stem cells (MSCs) to differentiate into endothelial cells was recently demonstrated. The aim of this study was to determine whether impaired differentiation of MSCs into endothelial cells in SSc might contribute to disease pathogenesis by decreasing endothelial repair. METHODS MSCs obtained from 7 SSc patients and 15 healthy controls were characterized. The number of colony-forming unit-fibroblastoid colonies was determined. After culture in endothelial-specific medium, the endothelial-like MSC (EL-MSC) phenotype was assessed according to the surface expression of vascular endothelial growth factor receptors (VEGFRs). Senescence, chemoinvasion, and capillary morphogenesis studies were also performed. RESULTS MSCs from SSc patients displayed the same phenotype and clonogenic activity as those from controls. In SSc MSCs, a decreased percentage of VEGFR-2+, CXCR4+, VEGFR-2+/CXCR4+ cells and early senescence was detected. After culturing, SSc EL-MSCs showed increased expression of VEGFR-1, VEGFR-2, and CXCR4, did not express CD31 or annexin V, and showed significantly decreased migration after specific stimuli. Moreover, the addition of VEGF and stromal cell-derived factor 1 to cultured SSc EL-MSCs increased their angiogenic potential less than that in controls. CONCLUSION Our data strongly suggest that endothelial repair may be affected in SSc. The possibility that endothelial progenitor cells could be used to increase vessel growth in chronic ischemic tissues may open up new avenues in the treatment of vascular damage caused by SSc.
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MESH Headings
- Adolescent
- Adult
- Case-Control Studies
- Cell Differentiation/physiology
- Cells, Cultured
- Cellular Senescence
- Chemokine CXCL12
- Chemokines, CXC/metabolism
- Endothelial Cells/physiology
- Endothelium, Vascular/metabolism
- Endothelium, Vascular/pathology
- Endothelium, Vascular/physiopathology
- Female
- Humans
- Immunophenotyping
- Male
- Mesenchymal Stem Cells/metabolism
- Mesenchymal Stem Cells/pathology
- Mesenchymal Stem Cells/physiology
- Middle Aged
- Neovascularization, Pathologic
- Phenotype
- Platelet Endothelial Cell Adhesion Molecule-1/metabolism
- Receptors, CXCR4/metabolism
- Receptors, Vascular Endothelial Growth Factor/metabolism
- Scleroderma, Systemic/pathology
- Scleroderma, Systemic/physiopathology
- Stem Cells/metabolism
- Stem Cells/pathology
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Seguin T, Braun T, Mira JP. [Endothelial progenitor cells: new biomarkers and potential therapy in intensive care]. Med Mal Infect 2007; 37:305-11. [PMID: 17512151 DOI: 10.1016/j.medmal.2007.03.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2007] [Accepted: 03/12/2007] [Indexed: 11/25/2022]
Abstract
One of the most important breakthroughs in the field of vascular biology in the last decade was the discovery of endothelial progenitor cells (EPCs). These angiogenic cells dwell in bone marrow, and may be found in the general circulation spontaneously or in response to various stimuli such as ischemia, growth factor, pro-inflammatory cytokines, and drugs such as statins. There is growing evidence that EPCs can differentiate into mature endothelial cells and facilitate endothelial repair and angiogenesis in vivo. In recent years, consistent publications have shown that EPCs provide both diagnostic and prognostic information with respect to cardiovascular diseases, acute lung injury, and sepsis. Activation of EPCs from the bone marrow or injection of these cells may be used as a therapeutic option for the treatment of ischemic cardiovascular diseases.
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Affiliation(s)
- T Seguin
- Service de réanimation médicale, CHU de Cochin-Saint-Vincent-de-Paul, Assistance publique - Hôpitaux de Paris, université Paris-Descartes, 27, rue du Faubourg-Saint-Jacques, 75679 Paris cedex 14, France
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Sturiale A, Coppolino G, Loddo S, Criseo M, Campo S, Crascì E, Bolignano D, Nostro L, Teti D, Buemi M. Effects of haemodialysis on circulating endothelial progenitor cell count. Blood Purif 2007; 25:242-51. [PMID: 17429198 DOI: 10.1159/000101697] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2006] [Accepted: 01/26/2007] [Indexed: 11/19/2022]
Abstract
During haemodialysis (HD) the endothelium is the first organ to sense and to be impaired by mechanical and immunological stimuli. We hypothesized that a single HD session induces mobilization of endothelial progenitor cells (EPCs) and that cardiovascular risk factors may influence this process. We quantified EPCs at different maturational stages (CD34+, CD133+/VEGFR2+) in blood samples from 30 patients, during HD and on the interdialytic day, and in 10 healthy volunteers. Samples were drawn at the start of HD, 1, 2 and 3 h after, at the end of HD and at 24 h on the interdialytic day. Patients were divided into two groups based on a recent risk scoring system (SCORE project): low-risk (LR) and high-risk groups (HR). HD patients showed a significantly reduced basal number of EPCs with respect to healthy volunteers. In contrast, we observed increasing EPCs during HD whereas they diminished on the interdialytic day. The EPC number was directly correlated with HD time progression. The EPC number during HD was increased in the HR group with respect to the LR group. We had a direct correlation between risk score and number of EPCs. Cardiovascular risk factors influenced the mobilization of stem cells from the bone marrow. This feature could be the direct consequence of an augmented request of stem cells to respond to the most important endothelial impairment but could also show a defective capacity of EPCs to home in and repair the sites of vascular injury.
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Affiliation(s)
- Alessio Sturiale
- Department of Internal Medicine, University of Messina, Messina, Italy
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Jang JH, Kim SK, Choi JE, Kim YJ, Lee HW, Kang SY, Park JS, Choi JH, Lim HY, Kim HC. Endothelial progenitor cell differentiation using cryopreserved, umbilical cord blood-derived mononuclear cells. Acta Pharmacol Sin 2007; 28:367-74. [PMID: 17302999 DOI: 10.1111/j.1745-7254.2007.00519.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
AIM To investigate the endothelial differentiation potentiality of umbilical cord blood (UCB), we induced the differentiation of endothelial progenitor cells (EPC) from cryopreserved UCB-derived mononuclear cells (MNC). METHODS MNC from cryopreserved UCB and peripheral blood (PB) were cultured in M199 medium with endothelial cell growth supplements for 14 d. EPC were characterized by RT-PCR, flow cytometry, and immunocytochemistry analysis. The proliferation of differentiated EPC was studied by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay, and vascular endothelial growth factor (VEGF) concentration was measured using an ELISA kit. Characteristics of UCB-derived EPC were compared with those of PB-derived EPC. RESULTS A number of round-shaped cells were loosely attached to the bottom after 24 h culture, and numerous spindleshaped cells began to appear from the round-shaped ones on d 7. Those cells expressed endothelial markers such as, Flt-1/VEGFR-1, ecNOS, VE-cadherin, von Willebrand factor, and secreted VEGF. The patterns of endothelial markers of EPC from PB and UCB did not show striking differences. The results of the proliferation and secretion of VEGF were also similar. CONCLUSION We successfully cultured UCB cells stored at -196 Celsius degree into cells with the quality of endothelial cells. Those EPC could be used for angiogenic therapeutics by activating adjacent endothelial cells and enhancing angiogenesis.
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Affiliation(s)
- Jun-Ho Jang
- Department of Hematology-Oncology, Ajou University, School of Medicine, Suwon 442749, Korea
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Fadini GP, Sartore S, Albiero M, Baesso I, Murphy E, Menegolo M, Grego F, Vigili de Kreutzenberg S, Tiengo A, Agostini C, Avogaro A. Number and function of endothelial progenitor cells as a marker of severity for diabetic vasculopathy. Arterioscler Thromb Vasc Biol 2006; 26:2140-6. [PMID: 16857948 DOI: 10.1161/01.atv.0000237750.44469.88] [Citation(s) in RCA: 335] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Peripheral arterial disease (PAD) is a threatening complication of diabetes. As endothelial progenitor cells (EPCs) are involved in neovasculogenesis and maintenance of vascular homeostasis, their impairment may have a role in the pathogenesis of diabetic vasculopathy. This study aimed to establish whether number and function of EPCs correlate with PAD severity in type 2 diabetic patients. METHODS AND RESULTS EPCs were defined by the expression of CD34, CD133 and KDR, and quantified by flow cytometry in 127 diabetic patients with and without PAD. PAD severity has been assessed as carotid atherosclerosis and clinical stage of leg atherosclerosis obliterans. Diabetic patients with PAD displayed a significant 53% reduction in circulating EPCs versus non-PAD patients, and EPC levels were negatively correlated with the degree of carotid stenosis and the stage of leg claudication. Moreover, the clonogenic and adhesion capacity of cultured EPCs were significantly lower in diabetic patients with PAD versus patients without. CONCLUSIONS This study demonstrates that EPC decrease is related to PAD severity and that EPC function is altered in diabetic subjects with PAD, strengthening the pathogenetic role of EPC dysregulation in diabetic vasculopathy. EPC count may be considered a novel biological marker of peripheral atherosclerosis in diabetes.
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Affiliation(s)
- Gian Paolo Fadini
- Department of Clinical and Experimental Medicine, Division of Metabolic Diseases, University of Padova, School of Medicine, Italy
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Coppola G, Corrado E, Muratori I, Tantillo R, Vitale G, Lo Coco L, Novo S. Increased levels of C-reactive protein and fibrinogen influence the risk of vascular events in patients with NIDDM. Int J Cardiol 2006; 106:16-20. [PMID: 16321660 DOI: 10.1016/j.ijcard.2004.12.051] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2004] [Accepted: 12/18/2004] [Indexed: 12/13/2022]
Abstract
AIM To evaluate the predictive role of hs-CRP and fibrinogen for cardio- and cerebrovascular events in a population of patients with type 2 diabetes. METHODS We studied 156 patients with type 2 diabetes, mean age 66+10 years, and 156 sex and age matched control subjects. Patients underwent physical examination, EKG, measurement of body mass index and blood pressure. A blood sample was drawn to evaluate glycaemia, total and HDL/LDL cholesterol, triglycerides, high sensitive C-reactive protein (hs-CRP), fibrinogen. Finally, patients underwent an ecocolordoppler examination of the common carotid arteries until the bifurcation. In a follow-up of 5+/-1.2 years we evaluated the following events: transient ischemic attack, ischemic stroke, stable or unstable angina, acute myocardial infarction, critical limb ischemia and cardiovascular death. RESULTS During the follow-up the prevalence of fatal (p<0.05) and non fatal events (p<0.0001) was higher in patients with diabetes in comparison with controls. The variables independently associated with non fatal events were: fibrinogen (p<0.0001), presence of asymptomatic carotid lesion (p<0.005), obesity (p<0.05) and plasma levels of hs-CRP (p<0.05), while fibrinogen (p<0.001) and age were (p<0.05) independently associated with fatal events. CONCLUSION Our data show that in patients with diabetes mellitus, that in the follow-up the presence of high plasma levels of hs-CRP and fibrinogen are predictive for fatal or non fatal events.
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Affiliation(s)
- Giuseppe Coppola
- Department of Internal Medicine, Cardiovascular and Nephro-Urological Diseases, University of Palermo, Chair of Cardiovascular Disease, Palermo, Italy.
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Okwuosa T, Williams KA. Coronary artery disease and nuclear imaging in renal failure. J Nucl Cardiol 2006; 13:150-5. [PMID: 16580948 DOI: 10.1007/bf02971236] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2006] [Indexed: 11/28/2022]
Affiliation(s)
- Tochi Okwuosa
- Department of Internal Medicine, University of Chicago, Chicago, Ill, USA
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Blann AD, Pretorius A. Circulating endothelial cells and endothelial progenitor cells: two sides of the same coin, or two different coins? Atherosclerosis 2006; 188:12-8. [PMID: 16487972 DOI: 10.1016/j.atherosclerosis.2005.12.024] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2005] [Revised: 12/16/2005] [Accepted: 12/19/2005] [Indexed: 11/15/2022]
Abstract
Circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs) are two populations of recently discovered endothelioid cells present in the blood. The former are thought to arise from the intima, the latter from the bone marrow. However, it is becoming clear that these are not in fact homogenous populations (e.g. differing degrees of apoptosis, necrosis and viability, differing expression of monocyte markers) but do in fact represent more than one species of endothelioid cell. Thus whilst originally defined by different criteria (e.g. CD146 by immunobeads, CD34 by flow cytometry) and the perception of independence, there is also growing evidence of some degree of commonality, i.e. some cells co-expressing CD146 and CD34. Furthermore, relationships between these two cells types and, for example, plasma and physiological indicators of vascular damage, and the risk factors for atherosclerosis, suggest a potential role for these cells in the pathophysiology of this disease, possibly as markers. The current document reviews this evidence, presenting a view of some degree of shared ancestry that may have implications for pathophysiology and cell biology.
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Affiliation(s)
- Andrew D Blann
- Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham B18 7QH, UK.
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Steiner S, Winkelmayer WC, Kleinert J, Grisar J, Seidinger D, Kopp CW, Watschinger B, Minar E, Hörl WH, Födinger M, Sunder-Plassmann G. Endothelial Progenitor Cells in Kidney Transplant Recipients. Transplantation 2006; 81:599-606. [PMID: 16495809 DOI: 10.1097/01.tp.0000198418.06383.e8] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Lower concentrations of endothelial progenitor cells (EPCs) may be associated with increased cardiovascular risk. EPC counts and their correlates have not yet been studied in kidney transplant recipients (KTR). METHODS We cross-sectionally studied EPC counts in 105 middle-aged KTR (mean estimated glomerular filtration rate 45.2 ml/min/1.73 m; range: 5.4 to 117.5). Using univariate and multivariate linear regression assuming a gamma distribution of the outcome, we examined the associations between counts of cultured EPCs and traditional cardiovascular disease risk factors (hypertension, diabetes, hyperlipidemia, smoking), kidney function, and immunosuppressive agents, amongst others. RESULTS The median count of cultured EPCs was 34 cells per high-power field (interquartile range: 19 to 64), comparable to healthy individuals. From multivariate analyses, we found independent inverse associations between counts of cultured EPCs and body mass index, mean arterial pressure, and history of cardiovascular disease. Statin use was associated with greater EPC counts, whereas patients receiving azathioprine or angiotensin II receptor treatment had lower EPC counts (all P<0.01). CONCLUSIONS This study suggests negative associations in KTR between EPC counts and body mass index, and blood pressure, whereas statin use was associated with greater EPC counts. These findings raise the hypothesis whether EPCs are responsible, at least in part, for the well established associations between these factors and cardiovascular outcomes in KTR.
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Affiliation(s)
- Sabine Steiner
- Division of Angiology, Department of Medicine II, Medical University Vienna, Vienna, Austria
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46
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Steiner S, Schaller G, Puttinger H, Födinger M, Kopp CW, Seidinger D, Grisar J, Hörl WH, Minar E, Vychytil A, Wolzt M, Sunder-Plassmann G. History of Cardiovascular Disease Is Associated With Endothelial Progenitor Cells in Peritoneal Dialysis Patients. Am J Kidney Dis 2005; 46:520-8. [PMID: 16129215 DOI: 10.1053/j.ajkd.2005.05.015] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2005] [Accepted: 05/09/2005] [Indexed: 11/11/2022]
Abstract
BACKGROUND It is unknown whether traditional cardiovascular disease risk factors influence the number of endothelial progenitor cells (EPCs) and whether numbers of EPCs correlate with endothelial function in patients with end-stage renal disease. METHODS In a cross-sectional study of 38 peritoneal dialysis patients, we examined numbers of circulating CD34+/KDR+/CD133+ cells, CD34+ hematopoietic stem cells, and EPCs cultured from peripheral blood. We also assessed conventional cardiovascular disease risk factors, such as history of vascular disease, diabetes, hypercholesterolemia, hypertension, and smoking. We determined endothelial function by measurement of endothelium-dependent and endothelium-independent reactivity of forearm resistance arteries by using strain-gauge plethysmography. RESULTS Numbers of EPCs cultured from peripheral blood and forearm blood flow reactivity did not differ between erythropoietin-treated peritoneal dialysis patients and healthy individuals. A history of vascular disease was associated with number of cultured EPCs, but other cardiovascular disease risk factors showed no association. Furthermore, there was no association of endothelial-dependent and endothelial-independent forearm blood flow reactivity with EPCs in peritoneal dialysis patients. CONCLUSION In this first study of EPCs in peritoneal dialysis patients, we found an association between history of vascular disease and EPCs, but no association of EPCs with endothelial function or other cardiovascular disease risk factors.
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Affiliation(s)
- Sabine Steiner
- Division of Angiology, Department of Medicine II, Medical University Vienna, Austria
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Nagy RD, Tsai BM, Wang M, Markel TA, Brown JW, Meldrum DR. Stem cell transplantation as a therapeutic approach to organ failure. J Surg Res 2005; 129:152-60. [PMID: 16045936 DOI: 10.1016/j.jss.2005.04.016] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2005] [Revised: 04/07/2005] [Accepted: 04/08/2005] [Indexed: 11/24/2022]
Abstract
BACKGROUND Stem cell transplantation is one of the next great frontiers for surgery. Stem cells, which are undifferentiated and self-renewing, have shown the ability to differentiate into cardiomyocytes, as well as many other cell types for potential therapeutic use by surgeons. MATERIALS AND METHODS As a result, stem cells have the potential to undo irreversible cellular damage, something traditional therapies could not cure. However, numerous issues must be resolved to permit safe and effective clinical application of stem cell therapy. These include the interpretation of cellular labeling, the origin of replicating myocytes, the homing mechanism of stem cells, and the differentiation process. RESULTS Successful translational research will depend on precise delivery of these cells in real time to the area of interest, e.g., the spinal cord, liver, or heart. Surgeons will be better able to excise and replace/regrow, rather than excise alone. As such, a basic understanding of stem cell biology will benefit the surgeon scientist and clinical surgeon. CONCLUSIONS The review: 1) discusses myocardial regeneration; 2) defines and categorizes stem cells; 3) presents evidence of stem cell transdifferentiation into cardiomyocytes; and, 4) delineates the therapeutic potential of stem cells in the treatment of ischemic heart disease.
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Affiliation(s)
- Ryan D Nagy
- Section of Cardiothoracic Surgery, Department of Surgery, Indianapolis, Indiana 46202, USA
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Abstract
One of the main goals in the treatment of myocardial ischemia is the development of effective therapy for angiogenesis and neovascularization. The first evidence demonstrating alleviation of myocardial ischemia and increased number of collateral blood vessels was reported in the early 90s following intra-coronary administration of basic fibroblast growth factor protein in canine. This study established the ground for extensive investigations to demonstrate the use of other angiogenic growth factor proteins, genes administered directly or incorporated in viruses, and more recently, endothelial progenitor stem cells (embryonic and adults). The positive results observed in animals failed, in most cases, to repeat themselves in clinical-trials in human patients. Therefore, additional experiments are warranted to allow full understanding of the mechanism underlying new blood vessel formation before further clinical studies are undertaken. This review will explore the milestones of angiogenic investigations and their clinical application.
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Affiliation(s)
- Mickey Scheinowitz
- Neufeld Cardiac Research Institute & Department of Biomedical Engineering, Tel Aviv University, Israel.
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Affiliation(s)
- Laurie G. Futterman
- The Division of Cardiology, Department of Medicine, University of Miami School of Medicine, Miami, Fla
| | - Louis Lemberg
- The Division of Cardiology, Department of Medicine, University of Miami School of Medicine, Miami, Fla
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