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Wang J, Zhan H, Wang M, Song H, Sun J, Zhao G. Sonic hedgehog signaling promotes angiogenesis of endothelial progenitor cells to improve pressure ulcers healing by PI3K/AKT/eNOS signaling. Aging (Albany NY) 2023; 15:10540-10548. [PMID: 37815888 PMCID: PMC10599757 DOI: 10.18632/aging.205093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 08/21/2023] [Indexed: 10/12/2023]
Abstract
BACKGROUND Pressure ulcer is a severe disease in the paralyzed and aging populations. Endothelial progenitor cells (EPCs) are able to regulate ulcer healing by modulating angiogenesis, but the molecular mechanism is still obscure. Sonic hedgehog (SHH) signaling contributes to angiogenesis in various diseases and has been identified to modulate EPCs function. Here, we aimed to explore the significance of SHH signaling in EPCs function during pressure ulcers. METHODS The EPCs were isolated and characterized by the expression of DiI-acLDL and bind fluorescein iso-thiocyanate UEA-1. Cell proliferation was detected by cell counting kit 8 (CCK-8). The DiI-acLDL and bind fluorescein iso-thiocyanate UEA-1 were analyzed by immunofluorescent analysis. The angiogenesis of EPCs was analyzed by tube formation assay. The pressure ulcers rat model was constructed, the wound injury was analyzed by H&E staining and angiogenesis was analyzed by the accumulation of CD31 based on immunofluorescent analysis. RESULTS The expression of patched-1 and Gli-1 was enhanced by SHH activator SAG but reduced by SHH inhibitor cyclopamine in the EPCsThe PI3K, Akt, eNOS expression and the Akt phosphorylation were induced by SAG, while the treatment of cyclopamine presented a reversed result. The proliferation and migration of EPCs were enhanced by SAG but repressed by cyclopamine or PI3K/AKT/eNOS signaling inhibitor Y294002, in which the co-treatment of Y294002 could reverse the effect of SAG. CONCLUSIONS Thus, we found that SHH signaling activated angiogenesis properties of EPCs to improve pressure ulcers healing by PI3K/AKT/eNOS signaling. SHH signaling may serve as the potential target for attenuating pressure ulcers.
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Affiliation(s)
- Jianhua Wang
- Department of Orthopaedics, Jinan Central Hospital, Jinan, Shandong Province, China
| | - Hongyan Zhan
- Department of B-Ultrasound, Fourth People’s Hospital of Jinan, Jinan, Shandong Province, China
| | - Mingming Wang
- Department of Orthopaedics, Tengzhou Central People’s Hospital, Tengzhou, Shandong Province, China
| | - Hua Song
- Department of Orthopaedics, Tengzhou Central People’s Hospital, Tengzhou, Shandong Province, China
| | - Jianhua Sun
- Department of Orthopaedics, Tengzhou Central People’s Hospital, Tengzhou, Shandong Province, China
| | - Gang Zhao
- Department of Orthopaedics, Jinan Central Hospital, Jinan, Shandong Province, China
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Microvesicles Produced by Natural Killer Cells Regulate the Formation of Blood Vessels. Bull Exp Biol Med 2020; 170:123-127. [PMID: 33237529 DOI: 10.1007/s10517-020-05017-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Indexed: 10/22/2022]
Abstract
We studied the effect of microvesicles derived from cells of the NK-92 cell line on the formation of tube-like structures by endothelial cells of the ЕА.Hy926 cell line. Microvesicles were isolated by differential centrifugation and their size was controlled by granulometric analysis using dynamic light scattering method. The effect of microvesicles produced by NK cells on angiogenesis was evaluated by cultural methods. In the course of the research, a model of co-culturing of microvesicles and endothelial cells on extracellular matrix Matrigel was developed. It was found that microvesicles derived from NK-92 cells promoted elongation of tube-like structures formed by endothelial ЕА.Hy926 cells. Microvesicles produced by NK cells can modulate functional activity of endothelial cells by affecting their ability to form blood vessels.
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Lazar E, Benedek T, Korodi S, Rat N, Lo J, Benedek I. Stem cell-derived exosomes - an emerging tool for myocardial regeneration. World J Stem Cells 2018; 10:106-115. [PMID: 30190780 PMCID: PMC6121000 DOI: 10.4252/wjsc.v10.i8.106] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 07/11/2018] [Accepted: 07/16/2018] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular diseases (CVDs) continue to represent the number one cause of death and disability in industrialized countries. The most severe form of CVD is acute myocardial infarction (AMI), a devastating disease associated with high mortality and disability. In a substantial proportion of patients who survive AMI, loss of functional cardiomyocytes as a result of ischaemic injury leads to ventricular failure, resulting in significant alteration to quality of life and increased mortality. Therefore, many attempts have been made in recent years to identify new tools for the regeneration of functional cardiomyocytes. Regenerative therapy currently represents the ultimate goal for restoring the function of damaged myocardium by stimulating the regeneration of the infarcted tissue or by providing cells that can generate new myocardial tissue to replace the damaged tissue. Stem cells (SCs) have been proposed as a viable therapy option in these cases. However, despite the great enthusiasm at the beginning of the SC era, justified by promising initial results, this therapy has failed to demonstrate a significant benefit in large clinical trials. One interesting finding of SC studies is that exosomes released by mesenchymal SCs (MSCs) are able to enhance the viability of cardiomyocytes after ischaemia/reperfusion injury, suggesting that the beneficial effects of MSCs in the recovery of functional myocardium could be related to their capacity to secrete exosomes. Ten years ago, it was discovered that exosomes have the unique property of transferring miRNA between cells, acting as miRNA nanocarriers. Therefore, exosome-based therapy has recently been proposed as an emerging tool for cardiac regeneration as an alternative to SC therapy in the post-infarction period. This review aims to discuss the emerging role of exosomes in developing innovative therapies for cardiac regeneration as well as their potential role as candidate biomarkers or for developing new diagnostic tools.
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Affiliation(s)
- Erzsebet Lazar
- Department of Internal Medicine, Clinic of Haematology and Bone Marrow Transplantation, University of Medicine and Pharmacy Tirgu Mures, Tirgu Mures 540042, Romania
| | - Theodora Benedek
- Department of Internal Medicine, Clinic of Cardiology, University of Medicine and Pharmacy Tirgu Mures, Tirgu Mures 540136, Romania
- Department of Advanced Research in Multimodality Cardiac Imaging, Cardio Med Medical Center, Tirgu Mures 540124, Romania
| | - Szilamer Korodi
- Department of Internal Medicine, Clinic of Cardiology, University of Medicine and Pharmacy Tirgu Mures, Tirgu Mures 540136, Romania
- Department of Advanced Research in Multimodality Cardiac Imaging, Cardio Med Medical Center, Tirgu Mures 540124, Romania
| | - Nora Rat
- Department of Internal Medicine, Clinic of Cardiology, University of Medicine and Pharmacy Tirgu Mures, Tirgu Mures 540136, Romania
- Department of Advanced Research in Multimodality Cardiac Imaging, Cardio Med Medical Center, Tirgu Mures 540124, Romania
| | - Jocelyn Lo
- Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, United States
| | - Imre Benedek
- Department of Internal Medicine, Clinic of Cardiology, University of Medicine and Pharmacy Tirgu Mures, Tirgu Mures 540136, Romania
- Department of Advanced Research in Multimodality Cardiac Imaging, Cardio Med Medical Center, Tirgu Mures 540124, Romania
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Insulin resistance adipocyte-derived exosomes aggravate atherosclerosis by increasing vasa vasorum angiogenesis in diabetic ApoE -/- mice. Int J Cardiol 2018; 265:181-187. [PMID: 29685689 DOI: 10.1016/j.ijcard.2018.04.028] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 03/19/2018] [Accepted: 04/05/2018] [Indexed: 11/23/2022]
Abstract
BACKGROUND Vasa vasorum (VV) angiogenesis is increased in type 2 diabetes mellitus (T2DM) and may promote atherosclerotic plaque rupture. We sought to determine whether insulin resistance adipocyte-derived exosomes (IRADEs) played a major role in modulating VV angiogenesis and the mechanisms involved. METHODS The characterization of IRADEs was performed by electron microscopy, NTA (Nanoparticle Tracking Analysis) and western blot. The cellular effects of IRADEs on angiogenesis were explored in human umbilical vein endothelial cells (HUVECs) and murine aortic endothelial cells (MAECs) in vitro. The roles of IRADEs in angiogenesis were demonstrated with aortic ring and matrigel plug assays ex vivo and the plaque burden, plaque stability and angiogenesis-related protein expression in vivo were evaluated by ultrasonography, immunohistochemistry and western blot. RESULTS The IRADEs had a cup-shaped morphology, could be taken up by HUVECs and atherosclerotic plaques, and promoted tube formation by shh in vitro. In the aortic ring and matrigel plug assays, angiogenesis was significantly increased in the IRADEs group. Exogenously administered shh-containing IRADEs increased VV angiogenesis, the plaque burden, the vulnerability index and the expression of angiogenesis-related factors, whereas these effects were attenuated by silencing shh in IRADEs. CONCLUSIONS In conclusion, IRADEs promote plaque burden and plaque vulnerability partly by inducing VV angiogenesis, which occurs partly through shh. Accordingly, the application of IRADEs may serve as a novel therapeutic approach to treat diabetic atherosclerosis.
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Kant RJ, Coulombe KLK. Integrated approaches to spatiotemporally directing angiogenesis in host and engineered tissues. Acta Biomater 2018; 69:42-62. [PMID: 29371132 PMCID: PMC5831518 DOI: 10.1016/j.actbio.2018.01.017] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 12/15/2017] [Accepted: 01/15/2018] [Indexed: 12/14/2022]
Abstract
The field of tissue engineering has turned towards biomimicry to solve the problem of tissue oxygenation and nutrient/waste exchange through the development of vasculature. Induction of angiogenesis and subsequent development of a vascular bed in engineered tissues is actively being pursued through combinations of physical and chemical cues, notably through the presentation of topographies and growth factors. Presenting angiogenic signals in a spatiotemporal fashion is beginning to generate improved vascular networks, which will allow for the creation of large and dense engineered tissues. This review provides a brief background on the cells, mechanisms, and molecules driving vascular development (including angiogenesis), followed by how biomaterials and growth factors can be used to direct vessel formation and maturation. Techniques to accomplish spatiotemporal control of vascularization include incorporation or encapsulation of growth factors, topographical engineering, and 3D bioprinting. The vascularization of engineered tissues and their application in angiogenic therapy in vivo is reviewed herein with an emphasis on the most densely vascularized tissue of the human body - the heart. STATEMENT OF SIGNIFICANCE Vascularization is vital to wound healing and tissue regeneration, and development of hierarchical networks enables efficient nutrient transfer. In tissue engineering, vascularization is necessary to support physiologically dense engineered tissues, and thus the field seeks to induce vascular formation using biomaterials and chemical signals to provide appropriate, pro-angiogenic signals for cells. This review critically examines the materials and techniques used to generate scaffolds with spatiotemporal cues to direct vascularization in engineered and host tissues in vitro and in vivo. Assessment of the field's progress is intended to inspire vascular applications across all forms of tissue engineering with a specific focus on highlighting the nuances of cardiac tissue engineering for the greater regenerative medicine community.
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Affiliation(s)
- Rajeev J Kant
- Center for Biomedical Engineering, School of Engineering, Brown University, Providence, RI, USA
| | - Kareen L K Coulombe
- Center for Biomedical Engineering, School of Engineering, Brown University, Providence, RI, USA.
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6
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Exosomes Mediate the Beneficial Effects of Exercise. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1000:333-353. [PMID: 29098629 DOI: 10.1007/978-981-10-4304-8_18] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
It is known that moderate exercise can prevent the development of cardiovascular diseases, but the exact molecular mechanisms mediating cardioprotective effect of exercise remain unknown. Emerging evidence suggests that exercise has great impact on the biogenesis of exosomes, which have been found in both interstitial fluid and circulation, and play important roles in cellular communication. Exosomes carry functional molecules such as mRNAs, microRNA, and specific proteins, which can be used in the early diagnosis and targeted therapy of a variety of diseases. Our review focus on the current knowledge on exosome production, secretion, uptake and how exercise influence exosome content. We also highlight recent research development in exosome based approach for cardiac repair.
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Qin Y, He YH, Hou N, Zhang GS, Cai Y, Zhang GP, Xiao Q, He LS, Li SJ, Yi Q, Luo JD. Sonic hedgehog improves ischemia-induced neovascularization by enhancing endothelial progenitor cell function in type 1 diabetes. Mol Cell Endocrinol 2016; 423:30-9. [PMID: 26773732 DOI: 10.1016/j.mce.2016.01.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Revised: 01/06/2016] [Accepted: 01/06/2016] [Indexed: 12/28/2022]
Abstract
The Sonic hedgehog (Shh) pathway is downregulated in type 1 diabetes, and it has been reported that augmentation of this pathway may alleviate diabetic complications. However, the cellular mechanisms underlying these protective effects are poorly understood. Recent studies indicate that impaired function of endothelial progenitor cells (EPCs) may contribute to cardiovascular problems in diabetes. We hypothesized that impaired Shh signaling contribute to endothelial progenitor cell dysfunction and that activating the Shh signaling pathway may rescue EPC function and promote diabetic neovascularization. Adult male C57/B6 mice and streptozotocin (STZ)-induced type 1 diabetic mice were used. Gli1 and Ptc1 protein levels were reduced in EPCs from diabetic mice, indicating inhibition of the Shh signaling pathway. EPC migration, tube formation ability, and mobilization were impaired in diabetic mice compared with non-diabetic controls (p < 0.05 vs control), and all were improved by in vivo administration of the Shh pathway receptor agonist SAG (p < 0.05 vs diabetes). SAG significantly increased capillary density and blood perfusion in the ischemic hindlimbs of diabetic mice (p < 0.05 vs diabetes). The AKT activity was lower in EPCs from diabetic mice than those from non-diabetic controls (p < 0.05 vs control). This decreased AKT activity led to an increased GSK-3β activity and degradation of the Shh pathway transcription factor Gli1/Gli2. SAG significantly increased the activity of AKT in EPCs. Our data clearly demonstrate that an impaired Shh pathway mediated by the AKT/GSK-3β pathway can contribute to EPC dysfunction in diabetes and thus activating the Shh signaling pathway can restore both the number and function of EPCs and increase neovascularization in type 1 diabetic mice.
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Affiliation(s)
- Yuan Qin
- Guangzhou Institute of Venoms, Guangzhou Medical University, Guangzhou 510182, China
| | - Yan-Huan He
- Guangzhou Institute of Venoms, Guangzhou Medical University, Guangzhou 510182, China
| | - Ning Hou
- Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, China
| | - Gen-Shui Zhang
- Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, China
| | - Yi Cai
- Guangzhou Institute of Venoms, Guangzhou Medical University, Guangzhou 510182, China
| | - Gui-Ping Zhang
- Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, China
| | - Qing Xiao
- Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, China
| | - Li-Shan He
- Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, China
| | - Su-Juan Li
- Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, China
| | - Quan Yi
- Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, China
| | - Jian-Dong Luo
- Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, China.
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Chistiakov DA, Orekhov AN, Bobryshev YV. Cardiac Extracellular Vesicles in Normal and Infarcted Heart. Int J Mol Sci 2016; 17:ijms17010063. [PMID: 26742038 PMCID: PMC4730308 DOI: 10.3390/ijms17010063] [Citation(s) in RCA: 130] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Revised: 12/10/2015] [Accepted: 12/18/2015] [Indexed: 02/06/2023] Open
Abstract
Heart is a complex assembly of many cell types constituting myocardium, endocardium and epicardium that intensively communicate to each other in order to maintain the proper cardiac function. There are many types of intercellular intracardiac signals, with a prominent role of extracellular vesicles (EVs), such as exosomes and microvesicles, for long-distant delivering of complex messages. Cardiomyocytes release EVs, whose content could significantly vary depending on the stimulus. In stress, such as hypoxia, inflammation or injury, cardiomyocytes increase secretion of EVs. In hypoxic conditions, cardiac EVs are enriched with angiogenic and prosurvival factors. In acute myocardial infarction (AMI), damaged cardiac muscle cells produce EVs with increased content of angiogenic, anti-apoptotic, mitogenic and growth factors in order to induce repair and healing of the infarcted myocardium. Exosomal microRNAs play a central role in cardiac regeneration. In AMI, circulating cardiac EVs abundantly contain cardiac-specific miRNAs that serve as indicators of cardiac damage and have a big diagnostic potential as AMI biomarkers. Cardioprotective and regenerative properties of exosomes derived from cardiac and non-cardiac stem/progenitor cells are very helpful to be used in cell-free cardiotherapy and regeneration of post-infarct myocardium.
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Affiliation(s)
- Dimitry A Chistiakov
- Department of Molecular Genetic Diagnostics and Cell Biology, Division of Laboratory Medicine, Institute of Pediatrics, Research Center for Children's Health, 119991 Moscow, Russia.
| | - Alexander N Orekhov
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia.
- Institute for Atherosclerosis Research, Skolkovo Innovative Center, 143025 Moscow, Russia.
- Department of Biophysics, Biological Faculty, Moscow State University, 119991 Moscow, Russia.
| | - Yuri V Bobryshev
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia.
- Faculty of Medicine, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
- School of Medicine, University of Western Sydney, Campbelltown, NSW 2560, Australia.
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Lichtenauer M, Goebel B, Fritzenwanger M, Förster M, Betge S, Lauten A, Figulla HR, Jung C. Simulated temporary hypoxia triggers the release of CD31+/Annexin+ endothelial microparticles: A prospective pilot study in humans. Clin Hemorheol Microcirc 2015; 61:83-90. [DOI: 10.3233/ch-141908] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Michael Lichtenauer
- Clinic of Internal Medicine II, Department of Cardiology, Paracelsus Medical University of Salzburg, Austria
| | - Bjoern Goebel
- Universitätsherzzentrum Thüringen, Clinic of Internal Medicine I, Department of Cardiology, Friedrich Schiller University Jena, Germany
| | - Michael Fritzenwanger
- Universitätsherzzentrum Thüringen, Clinic of Internal Medicine I, Department of Cardiology, Friedrich Schiller University Jena, Germany
| | - Martin Förster
- Universitätsherzzentrum Thüringen, Clinic of Internal Medicine I, Department of Cardiology, Friedrich Schiller University Jena, Germany
| | - Stefan Betge
- Universitätsherzzentrum Thüringen, Clinic of Internal Medicine I, Department of Cardiology, Friedrich Schiller University Jena, Germany
| | - Alexander Lauten
- Universitätsherzzentrum Thüringen, Clinic of Internal Medicine I, Department of Cardiology, Friedrich Schiller University Jena, Germany
| | - Hans-Reiner Figulla
- Universitätsherzzentrum Thüringen, Clinic of Internal Medicine I, Department of Cardiology, Friedrich Schiller University Jena, Germany
| | - Christian Jung
- Universitätsherzzentrum Thüringen, Clinic of Internal Medicine I, Department of Cardiology, Friedrich Schiller University Jena, Germany
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10
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Zhou BD, Guo G, Zheng LM, Zu LY, Gao W. Microparticles as novel biomarkers and therapeutic targets in coronary heart disease. Chin Med J (Engl) 2015; 128:267-72. [PMID: 25591573 PMCID: PMC4837849 DOI: 10.4103/0366-6999.149231] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Affiliation(s)
| | | | | | - Ling-Yun Zu
- Department of Cardiology, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Peking University Third Hospital, Beijing 100191, China
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11
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Extracellular vesicles as new pharmacological targets to treat atherosclerosis. Eur J Pharmacol 2015; 763:90-103. [PMID: 26142082 DOI: 10.1016/j.ejphar.2015.06.047] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 05/13/2015] [Accepted: 06/25/2015] [Indexed: 01/09/2023]
Abstract
Extracellular vesicles released by most cell types, include apoptotic bodies (ABs), microvesicles (MVs) and exosomes. They play a crucial role in physiology and pathology, contributing to "cell-to-cell" communication by modifying the phenotype and the function of target cells. Thus, extracellular vesicles participate in the key processes of atherosclerosis from endothelial dysfunction, vascular wall inflammation to vascular remodeling. The purpose of this review is to summarize recent findings on extracellular vesicle formation, structure, release and clearance. We focus on the deleterious and beneficial effects of extracellular vesicles in the development of atherosclerosis. The potential role of extracellular vesicles as biomarkers and pharmacological targets, their innate therapeutic capacity, or their use for novel drug delivery devices in atherosclerotic cardiovascular diseases will also be discussed.
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12
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Morhayim J, Baroncelli M, van Leeuwen JP. Extracellular vesicles: Specialized bone messengers. Arch Biochem Biophys 2014; 561:38-45. [DOI: 10.1016/j.abb.2014.05.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Revised: 04/16/2014] [Accepted: 05/08/2014] [Indexed: 12/22/2022]
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Fleury A, Martinez MC, Le Lay S. Extracellular vesicles as therapeutic tools in cardiovascular diseases. Front Immunol 2014; 5:370. [PMID: 25136343 PMCID: PMC4120684 DOI: 10.3389/fimmu.2014.00370] [Citation(s) in RCA: 93] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Accepted: 07/18/2014] [Indexed: 12/19/2022] Open
Abstract
Extracellular vesicles (EVs), including microvesicles (MVs) and exosomes, are small vesicles secreted from a wide variety of cells. Whereas MVs are particles released by the outward budding of the plasma membrane, exosomes are derived from endocytic compartments. Secretion of EVs can be enhanced by specific stimuli, and increased plasma circulating levels of EVs have been correlated with pathophysiological situations. MVs, already present in the blood of healthy individuals, are considerably elevated in several cardiovascular diseases associated with inflammation, suggesting that they can mediate deleterious effects such as endothelial dysfunction or thrombosis. Nonetheless, very recent studies also demonstrate that MVs may act as biological information vectors transferring proteins or genetic material to maintain cell homeostasis, favor cell repair, or even promote angiogenesis. Additionally, exosomes have also been shown to have pro-angiogenic and cardio-protective properties. These beneficial effects, therefore, reveal the potential therapeutical use of EVs in the field of cardiovascular medicine and regenerative therapy. In this review, we will provide an update of cellular processes modulated by EVs of specific interest in the treatment of cardiovascular pathologies. A special focus will be made on the morphogen sonic hedgehog (Shh) associated with EVs (EVsShh+), which have been shown to mediate many pro-angiogenic effects. In addition to offer a potential source of cardiovascular markers, therapeutical potential of EVs reveal exciting opportunities to deliver specific agents by non-immunogenic means to cardiovascular system.
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Affiliation(s)
- Audrey Fleury
- INSERM U1063 "Oxidative Stress and Metabolic Pathologies," Institut de Biologie en Santé, Université d'Angers , Angers , France
| | - Maria Carmen Martinez
- INSERM U1063 "Oxidative Stress and Metabolic Pathologies," Institut de Biologie en Santé, Université d'Angers , Angers , France
| | - Soazig Le Lay
- INSERM U1063 "Oxidative Stress and Metabolic Pathologies," Institut de Biologie en Santé, Université d'Angers , Angers , France
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14
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Giulivi C. Grand challenges in cellular biochemistry: the "next-gen" biochemistry. Front Chem 2014; 2:22. [PMID: 24809045 PMCID: PMC4010732 DOI: 10.3389/fchem.2014.00022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Accepted: 04/10/2014] [Indexed: 01/10/2023] Open
Affiliation(s)
- Cecilia Giulivi
- Department of Molecular Biosciences, University of California, DavisDavis, CA, USA
- Medical Investigations of Neurodevelopmental Disorders Institute, University of California, DavisDavis, CA, USA
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15
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Shifrin DA, Demory Beckler M, Coffey RJ, Tyska MJ. Extracellular vesicles: communication, coercion, and conditioning. Mol Biol Cell 2013; 24:1253-9. [PMID: 23630232 PMCID: PMC3639038 DOI: 10.1091/mbc.e12-08-0572] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Cells communicate with neighboring cells and condition their local environment by secreting soluble factors into the extracellular space. These well-studied facets of cell biology are essential for the establishment and maintenance of physiological homeostasis. However, accumulating evidence has revealed that specific ligands, enzymes, and macromolecules are distributed into the extracellular space by virtue of their association with small vesicles, which are released by a variety of cell types. Although the biological significance of such vesicles was initially debated, purification and subsequent functional studies have shown that these extracellular vesicles are bioactive organelles carrying a wide range of protein and nucleic acid cargoes. In many cases these vesicles are laden with molecules that are involved in cell signaling, although other diverse functions are being revealed at a rapid pace. In this Perspective, we discuss recent developments in the understanding of the major pathways of extracellular vesicle biogenesis and how these vesicles contribute to the maintenance of physiological homeostasis.
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Affiliation(s)
- David A Shifrin
- Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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Wendler F, Bota-Rabassedas N, Franch-Marro X. Cancer becomes wasteful: emerging roles of exosomes(†) in cell-fate determination. J Extracell Vesicles 2013; 2:22390. [PMID: 24223259 PMCID: PMC3823269 DOI: 10.3402/jev.v2i0.22390] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Revised: 08/18/2013] [Accepted: 08/21/2013] [Indexed: 11/15/2022] Open
Abstract
Extracellular vesicles (EVs), including exosomes, have been widely recognized for their role in intercellular communication of the immune response system. In the past few years, significance has been given to exosomes in the induction and modulation of cell-fate-inducing signalling pathways, such as the Hedgehog (Hh), Wnts, Notch, transforming growth factor (TGF-β), epidermal growth factor (EGF) and fibroblast growth factor (FGF) pathways, placing them in the wider context of development and also of cancer. These protein families induce signalling cascades responsible for tissue specification, homeostasis and maintenance. Exosomes contribute to cell-fate signal secretion, and vice versa exosome secretion can be induced by these proteins. Interestingly, exosomes can also transfer their mRNA to host cells or modulate the signalling pathways directly by the removal of downstream effector molecules from the cell. Surprisingly, much of what we know about the function of exosomes in cell determination is gathered from pathological transformed cancer cells and wound healing while data about their biogenesis and biology in normal developing and adult tissue lag behind. In this report, we will summarize some of the published literature and point to current advances and questions in this fast-developing topic. In a brief foray, we will also update and shortly discuss their potential in diagnosis and targeted cancer treatment.
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Affiliation(s)
- Franz Wendler
- past address: CNRS UMR, Inserm UMR, Institute de Biologie Valrose (IBV), Centre de Biochemie, Nice, France
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Riobo NA. Cholesterol and its derivatives in Sonic Hedgehog signaling and cancer. Curr Opin Pharmacol 2012; 12:736-41. [PMID: 22832232 DOI: 10.1016/j.coph.2012.07.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2012] [Revised: 07/02/2012] [Accepted: 07/03/2012] [Indexed: 10/28/2022]
Abstract
The connection between the Hedgehog (HH) pathway and cholesterol has been recognized since the early days that shaped our current understanding of this unique pathway. Cholesterol and related lipids are intricately linked to HH signaling: from the role of cholesterol in HH biosynthesis to the modulation of HH signal reception and transduction by other sterols, passing by the phylogenetic relationships among many components of the HH pathway that resemble or contain lipid-binding domains. Here I review the connections between HH signaling, cholesterol and its derivatives and analyze the potential implications for HH-dependent cancers.
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Affiliation(s)
- Natalia A Riobo
- Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA.
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