|
1
|
Hattori Y, Yamada H, Mori H, Oba S, Yokota K, Omi M, Yamamoto Y, Toyama K, Ohnaka M, Takahashi K, Imai H. The effect of fibroblast growth factor 2 on neovascular vessels depends on the stage of angiogenesis. Heliyon 2024; 10:e39843. [PMID: 39553576 PMCID: PMC11566843 DOI: 10.1016/j.heliyon.2024.e39843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 10/23/2024] [Accepted: 10/24/2024] [Indexed: 11/19/2024] Open
Abstract
Objective The exact relationship between fibroblast growth factor 2 (FGF2) and choroidal neovascularization (CNV) remains unclear. In this study, using optical coherence tomography angiography (OCTA) and FGF2-tg mice which are transgenic mice with a rhodopsin promoter/FGF2 gene fusion, we aimed to investigate the dynamics of FGF2's role in angiogenesis over time. Methods We developed laser-induced CNV models of FGF2-tg and wild-type (WT) mice and then separated them into two groups using different laser photocoagulation (PC) conditions. The first group received 3 intense PC shots (1st PC) altogether (one-time PC group), while the other group received 3 intense PC shots (1st PC) followed by 6 additional weak PC shots (2 nd PC) on the 7th day after 1st PC (two-times PC group). Results Using OCTA to observe vessel changes within the same individual over time, there was no difference in the timing of vessel transition from the CNV development phase to the CNV regression phase between FGF2-tg and WT mice in the one-time PC group. In contrast, the neovascular vessels in the two-times PC group of FGF2-tg mice were maintained at least 28 days post-2nd PC without regression. In addition, mature vessels surrounded by PDGFRβ positive pericytes and α-SMA positive smooth muscle cells were observed. Real-time qPCR showed a substantial increase in apelin mRNA expression in the one-time PC group of FGF2-tg, rather than VEGF-A (p < 0.05, n = 5 or 6). Moreover, the expression levels of PDGFRβ, apelin, and Ang1 were significantly higher in FGF2-tg mice of two-times PC group than in WT mice (p < 0.05, n = 5 or 6). Conclusions FGF2 not only promotes neovascularization via the apelin/APJ system, which is independent of VEGF signaling pathway, but also helps maintain and stabilize pre-existing neovascular vessels by stimulating PDGFRβ and Ang1. The effect of FGF2 on the neovascular vessels depends on the stage of angiogenesis.
Collapse
Affiliation(s)
- Yuki Hattori
- Department of Ophthalmology, Kansai Medical University, Osaka, Japan
| | | | - Hidetsugu Mori
- Department of Ophthalmology, Kansai Medical University, Osaka, Japan
| | - Shinpei Oba
- Department of Ophthalmology, Kansai Medical University, Osaka, Japan
| | - Kaito Yokota
- Department of Ophthalmology, Kansai Medical University, Osaka, Japan
| | - Masatoshi Omi
- Department of Ophthalmology, Kansai Medical University, Osaka, Japan
| | - Yuichi Yamamoto
- Department of Ophthalmology, Kansai Medical University, Osaka, Japan
| | - Keiko Toyama
- Department of Ophthalmology, Kansai Medical University, Osaka, Japan
| | - Masayuki Ohnaka
- Department of Ophthalmology, Kansai Medical University, Osaka, Japan
| | - Kanji Takahashi
- Department of Ophthalmology, Kansai Medical University, Osaka, Japan
| | - Hisanori Imai
- Department of Ophthalmology, Kansai Medical University, Osaka, Japan
| |
Collapse
|
|
2
|
Zhu A, Baur C, Götz P, Elbs K, Lasch M, Faro A, Preissner KT, Deindl E. The Complement System Is Essential for Arteriogenesis by Enhancing Sterile Inflammation as a Relevant Step in Collateral Artery Growth. Cells 2024; 13:1405. [PMID: 39272977 PMCID: PMC11394660 DOI: 10.3390/cells13171405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 08/13/2024] [Accepted: 08/22/2024] [Indexed: 09/15/2024] Open
Abstract
Arteriogenesis is an inflammatory driven mechanism, describing the growth of a natural bypass from pre-existing collateral arteries to compensate for an occluded artery. The complement system component C3 is a potent natural inflammatory activator. Here, we investigated its impact on the process of collateral artery growth using C3-deficient (C3 -/-) and wildtype control mice in a murine hindlimb model of arteriogenesis. Induction of arteriogenesis by unilateral femoral artery ligation resulted in decreased perfusion recovery in C3 -/- mice on day 7 as shown by Laser Doppler imaging. Immunofluorescence staining revealed a reduced vascular cell proliferation in C3 -/- mice. Gene expression analysis displayed a significant reduction in monocyte chemoattractant protein-1 (MCP-1) expression in C3 -/- mice. Interestingly, 3 days after induction of arteriogenesis, the number of macrophages (CD68+) recruited to growing collaterals was not affected by C3 deficiency. However, a significant reduction in inflammatory M1-like polarized macrophages (CD68+/MRC1-) was noted. Forced mast cell activation by Compound 48/80 as well as exogenous MCP-1 application rescued the number of M1-like polarized macrophages along with perfusion recovery in C3 -/- mice. In summary, this study demonstrates that complement C3 influences arteriogenesis by mediating MCP-1 expression, which is essential for the induction and enhancement of sterile inflammation.
Collapse
Affiliation(s)
- Amanda Zhu
- Institute of Surgical Research at the Walter Brendel Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (A.Z.); (C.B.); (P.G.); (K.E.); (M.L.); (A.F.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Carolin Baur
- Institute of Surgical Research at the Walter Brendel Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (A.Z.); (C.B.); (P.G.); (K.E.); (M.L.); (A.F.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Philipp Götz
- Institute of Surgical Research at the Walter Brendel Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (A.Z.); (C.B.); (P.G.); (K.E.); (M.L.); (A.F.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Katharina Elbs
- Institute of Surgical Research at the Walter Brendel Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (A.Z.); (C.B.); (P.G.); (K.E.); (M.L.); (A.F.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Manuel Lasch
- Institute of Surgical Research at the Walter Brendel Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (A.Z.); (C.B.); (P.G.); (K.E.); (M.L.); (A.F.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
| | - Anna Faro
- Institute of Surgical Research at the Walter Brendel Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (A.Z.); (C.B.); (P.G.); (K.E.); (M.L.); (A.F.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Klaus T. Preissner
- Department of Cardiology, Kerckhoff-Heart Research Institute, Faculty of Medicine, Justus-Liebig-University, 35392 Giessen, Germany;
| | - Elisabeth Deindl
- Institute of Surgical Research at the Walter Brendel Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (A.Z.); (C.B.); (P.G.); (K.E.); (M.L.); (A.F.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| |
Collapse
|
|
3
|
Bui TA, Jickling GC, Winship IR. Neutrophil dynamics and inflammaging in acute ischemic stroke: A transcriptomic review. Front Aging Neurosci 2022; 14:1041333. [PMID: 36620775 PMCID: PMC9813499 DOI: 10.3389/fnagi.2022.1041333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 11/28/2022] [Indexed: 12/24/2022] Open
Abstract
Stroke is among the leading causes of death and disability worldwide. Restoring blood flow through recanalization is currently the only acute treatment for cerebral ischemia. Unfortunately, many patients that achieve a complete recanalization fail to regain functional independence. Recent studies indicate that activation of peripheral immune cells, particularly neutrophils, may contribute to microcirculatory failure and futile recanalization. Stroke primarily affects the elderly population, and mortality after endovascular therapies is associated with advanced age. Previous analyses of differential gene expression across injury status and age identify ischemic stroke as a complex age-related disease. It also suggests robust interactions between stroke injury, aging, and inflammation on a cellular and molecular level. Understanding such interactions is crucial in developing effective protective treatments. The global stroke burden will continue to increase with a rapidly aging human population. Unfortunately, the mechanisms of age-dependent vulnerability are poorly defined. In this review, we will discuss how neutrophil-specific gene expression patterns may contribute to poor treatment responses in stroke patients. We will also discuss age-related transcriptional changes that may contribute to poor clinical outcomes and greater susceptibility to cerebrovascular diseases.
Collapse
Affiliation(s)
- Truong An Bui
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
| | - Glen C. Jickling
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
- Department of Medicine, Division of Neurology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Ian R. Winship
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
| |
Collapse
|
|
4
|
Spiliopoulos S, Festas G, Paraskevopoulos I, Mariappan M, Brountzos E. Overcoming ischemia in the diabetic foot: Minimally invasive treatment options. World J Diabetes 2021; 12:2011-2026. [PMID: 35047116 PMCID: PMC8696640 DOI: 10.4239/wjd.v12.i12.2011] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 06/13/2021] [Accepted: 10/31/2021] [Indexed: 02/06/2023] Open
Abstract
As the global burden of diabetes is rapidly increasing, the incidence of diabetic foot ulcers is continuously increasing as the mean age of the world population increases and the obesity epidemic advances. A significant percentage of diabetic foot ulcers are caused by mixed micro and macro-vascular dysfunction leading to impaired perfusion of foot tissue. Left untreated, chronic limb-threatening ischemia has a poor prognosis and is correlated with limb loss and increased mortality; prompt treatment is required. In this review, the diagnostic challenges in diabetic foot disease are discussed and available data on minimally invasive treatment options such as endovascular revascularization, stem cells, and gene therapy are examined.
Collapse
Affiliation(s)
- Stavros Spiliopoulos
- Second Department of Radiology, Interventional Radiology Unit, Attikon University Hospital, Athens 12461, Greece
| | - Georgios Festas
- Second Department of Radiology, Interventional Radiology Unit, Attikon University Hospital, Athens 12461, Greece
| | - Ioannis Paraskevopoulos
- Department of Clinical Radiology, Interventional Radiology Unit, Aberdeen Royal Infirmary, NHS Grampian, Aberdeen AB25 2ZN, United Kingdom
| | - Martin Mariappan
- Department of Clinical Radiology, Interventional Radiology Unit, Aberdeen Royal Infirmary, NHS Grampian, Aberdeen AB25 2ZN, United Kingdom
| | - Elias Brountzos
- Second Department of Radiology, School of Medicine; National and Kapodistrian University of Athens, Athens 12461, Greece
| |
Collapse
|
|
5
|
Role of Vascular Smooth Muscle Cell Phenotype Switching in Arteriogenesis. Int J Mol Sci 2021; 22:ijms221910585. [PMID: 34638923 PMCID: PMC8508942 DOI: 10.3390/ijms221910585] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 09/26/2021] [Accepted: 09/27/2021] [Indexed: 12/12/2022] Open
Abstract
Arteriogenesis is one of the primary physiological means by which the circulatory collateral system restores blood flow after significant arterial occlusion in peripheral arterial disease patients. Vascular smooth muscle cells (VSMCs) are the predominant cell type in collateral arteries and respond to altered blood flow and inflammatory conditions after an arterial occlusion by switching their phenotype between quiescent contractile and proliferative synthetic states. Maintaining the contractile state of VSMC is required for collateral vascular function to regulate blood vessel tone and blood flow during arteriogenesis, whereas synthetic SMCs are crucial in the growth and remodeling of the collateral media layer to establish more stable conduit arteries. Timely VSMC phenotype switching requires a set of coordinated actions of molecular and cellular mediators to result in an expansive remodeling of collaterals that restores the blood flow effectively into downstream ischemic tissues. This review overviews the role of VSMC phenotypic switching in the physiological arteriogenesis process and how the VSMC phenotype is affected by the primary triggers of arteriogenesis such as blood flow hemodynamic forces and inflammation. Better understanding the role of VSMC phenotype switching during arteriogenesis can identify novel therapeutic strategies to enhance revascularization in peripheral arterial disease.
Collapse
|
|
6
|
Zhang X, Zheng Y, Geng C, Guan J, Wang L, Zhang X, Cheng Y, Li J, Lu X. Isometric exercise promotes arteriogenesis in rats after myocardial infarction. J Biomed Res 2021; 35:436-447. [PMID: 34776455 PMCID: PMC8637657 DOI: 10.7555/jbr.35.20210062] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Isometric exercise (IE) is a promising intervention of noninvasive revascularization in patients with acute myocardial infarction (AMI). This study aimed to investigate the impact and mechanisms of IE training on arteriogenesis in AMI. Male Sprague-Dawley rats were randomly assigned into the sham-operation group (SO), myocardial infarction (MI) group, and 13 IE subgroups treated according to training intensity, frequency, duration, or monocyte chemoattractant protein-1 (MCP-1), or/and fibroblast growth factor-2 (FGF-2) inhibitors for eight weeks. Our results demonstrated that the IE group achieved superior improvement compared with the MI group in terms of left ventricular ejection fraction (LVEF), myocardial infarction size (MIS), arterial density (AD), monocytes (MNCs), smooth muscle cells (SMCs), endothelial cells (ECs), relative collateral blood flow (RCBF), MCP-1, and FGF-2 at the endpoint. Positive correlations between MCP-1 and MNCs, MNCs and FGF-2, FGF-2 and SMCs, SMCs and AD, as well as AD and RCBF were observed. This study demonstrated that with MI of 100% load 20 times daily for eight weeks, the arteriogenesis was improved, which may be attributed to the recruitment of MNCs and SMCs in remote ischemic myocardium caused by increases in MCP-1 and FGF-2 expression.
Collapse
Affiliation(s)
- Xintong Zhang
- Department of Rehabilitation Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Yu Zheng
- Department of Rehabilitation Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Canru Geng
- Department of Rehabilitation Medicine, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215000, China
| | - Juntao Guan
- Department of Rehabilitation Medicine, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215000, China
| | - Lu Wang
- Department of Rehabilitation Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Xiu Zhang
- Department of Rehabilitation Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Yihui Cheng
- Department of Rehabilitation Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Jian'an Li
- Department of Rehabilitation Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Xiao Lu
- Department of Rehabilitation Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| |
Collapse
|
|
7
|
Recruitment and maturation of the coronary collateral circulation: Current understanding and perspectives in arteriogenesis. Microvasc Res 2020; 132:104058. [PMID: 32798552 DOI: 10.1016/j.mvr.2020.104058] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 06/09/2020] [Accepted: 08/11/2020] [Indexed: 12/13/2022]
Abstract
The coronary collateral circulation is a rich anastomotic network of primitive vessels which have the ability to augment in size and function through the process of arteriogenesis. In this review, we evaluate the current understandings of the molecular and cellular mechanisms by which this process occurs, specifically focussing on elevated fluid shear stress (FSS), inflammation, the redox state and gene expression along with the integrative, parallel and simultaneous process by which this occurs. The initiating step of arteriogenesis occurs following occlusion of an epicardial coronary artery, with an increase in FSS detected by mechanoreceptors within the endothelium. This must occur within a 'redox window' where an equilibrium of oxidative and reductive factors are present. These factors initially result in an inflammatory milieu, mediated by neutrophils as well as lymphocytes, with resultant activation of a number of downstream molecular pathways resulting in increased expression of proteins involved in monocyte attraction and adherence; namely vascular cell adhesion molecule 1 (VCAM-1), monocyte chemoattractant protein 1 (MCP-1) and transforming growth factor beta (TGF-β). Once monocytes and other inflammatory cells adhere to the endothelium they enter the extracellular matrix and differentiate into macrophages in an effort to create a favourable environment for vessel growth and development. Activated macrophages secrete inflammatory cytokines such as tumour necrosis factor-α (TNF-α), growth factors such as fibroblast growth factor-2 (FGF-2) and matrix metalloproteinases. Finally, vascular smooth muscle cells proliferate and switch to a contractile phenotype, resulting in an increased diameter and functionality of the collateral vessel, thereby allowing improved perfusion of the distal myocardium subtended by the occluded vessel. This simultaneously reduces FSS within the collateral vessel, inhibiting further vessel growth.
Collapse
|
|
8
|
Contribution of the Potassium Channels K V1.3 and K Ca3.1 to Smooth Muscle Cell Proliferation in Growing Collateral Arteries. Cells 2020; 9:cells9040913. [PMID: 32276492 PMCID: PMC7226779 DOI: 10.3390/cells9040913] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 03/21/2020] [Accepted: 04/03/2020] [Indexed: 12/20/2022] Open
Abstract
Collateral artery growth (arteriogenesis) involves the proliferation of vascular endothelial cells (ECs) and smooth muscle cells (SMCs). Whereas the proliferation of ECs is directly related to shear stress, the driving force for arteriogenesis, little is known about the mechanisms of SMC proliferation. Here we investigated the functional relevance of the potassium channels KV1.3 and KCa3.1 for SMC proliferation in arteriogenesis. Employing a murine hindlimb model of arteriogenesis, we found that blocking KV1.3 with PAP-1 or KCa3.1. with TRAM-34, both interfered with reperfusion recovery after femoral artery ligation as shown by Laser-Doppler Imaging. However, only treatment with PAP-1 resulted in a reduced SMC proliferation. qRT-PCR results revealed an impaired downregulation of α smooth muscle-actin (αSM-actin) and a repressed expression of fibroblast growth factor receptor 1 (Fgfr1) and platelet derived growth factor receptor b (Pdgfrb) in growing collaterals in vivo and in primary murine arterial SMCs in vitro under KV1.3. blockade, but not when KCa3.1 was blocked. Moreover, treatment with PAP-1 impaired the mRNA expression of the cell cycle regulator early growth response-1 (Egr1) in vivo and in vitro. Together, these data indicate that KV1.3 but not KCa3.1 contributes to SMC proliferation in arteriogenesis.
Collapse
|
|
9
|
Heuslein JL, Gorick CM, Price RJ. Epigenetic regulators of the revascularization response to chronic arterial occlusion. Cardiovasc Res 2020; 115:701-712. [PMID: 30629133 DOI: 10.1093/cvr/cvz001] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 12/13/2018] [Accepted: 01/03/2019] [Indexed: 12/12/2022] Open
Abstract
Peripheral arterial disease (PAD) is the leading cause of lower limb amputation and estimated to affect over 202 million people worldwide. PAD is caused by atherosclerotic lesions that occlude large arteries in the lower limbs, leading to insufficient blood perfusion of distal tissues. Given the severity of this clinical problem, there has been long-standing interest in both understanding how chronic arterial occlusions affect muscle tissue and vasculature and identifying therapeutic approaches capable of restoring tissue composition and vascular function to a healthy state. To date, the most widely utilized animal model for performing such studies has been the ischaemic mouse hindlimb. Despite not being a model of PAD per se, the ischaemic hindlimb model does recapitulate several key aspects of PAD. Further, it has served as a valuable platform upon which we have built much of our understanding of how chronic arterial occlusions affect muscle tissue composition, muscle regeneration and angiogenesis, and collateral arteriogenesis. Recently, there has been a global surge in research aimed at understanding how gene expression is regulated by epigenetic factors (i.e. non-coding RNAs, histone post-translational modifications, and DNA methylation). Thus, perhaps not unexpectedly, many recent studies have identified essential roles for epigenetic factors in regulating key responses to chronic arterial occlusion(s). In this review, we summarize the mechanisms of action of these epigenetic regulators and highlight several recent studies investigating the role of said regulators in the context of hindlimb ischaemia. In addition, we focus on how these recent advances in our understanding of the role of epigenetics in regulating responses to chronic arterial occlusion(s) can inform future therapeutic applications to promote revascularization and perfusion recovery in the setting of PAD.
Collapse
Affiliation(s)
- Joshua L Heuslein
- Department of Biomedical Engineering, University of Virginia, 415 Lane Rd, Box 800759, Health System, Charlottesville, VA, USA
| | - Catherine M Gorick
- Department of Biomedical Engineering, University of Virginia, 415 Lane Rd, Box 800759, Health System, Charlottesville, VA, USA
| | - Richard J Price
- Department of Biomedical Engineering, University of Virginia, 415 Lane Rd, Box 800759, Health System, Charlottesville, VA, USA
| |
Collapse
|
|
10
|
Abstract
Myocardial ischemia and peripheral vascular disease persist as significant clinical problems despite improved medical, surgical, and endovascular therapies. Advances in our understanding of the biological mechanisms that govern capillary neovascularization and collateral artery growth have enabled molecular therapies for revascularizing ischemic tissues. Generally known as therapeutic angiogenesis, this review summarizes the essential pre-clinical research and the major clinical trials of molecular therapies for ischemic disease. Early clinical experience has established the proof of principle, however, inconsistent and modest improvements in clinical outcomes have exposed the complexity of neovascularization and problems with transitioning basic science to clinical applicability.
Collapse
Affiliation(s)
- Shant M Vartanian
- Division of Vascular Surgery, University of California, San Francisco, California 94143-0104, USA.
| | | |
Collapse
|
|
11
|
Ren B, Rose JB, Liu Y, Jaskular-Sztul R, Contreras C, Beck A, Chen H. Heterogeneity of Vascular Endothelial Cells, De Novo Arteriogenesis and Therapeutic Implications in Pancreatic Neuroendocrine Tumors. J Clin Med 2019; 8:jcm8111980. [PMID: 31739580 PMCID: PMC6912347 DOI: 10.3390/jcm8111980] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 11/08/2019] [Accepted: 11/12/2019] [Indexed: 02/07/2023] Open
Abstract
Arteriogenesis supplies oxygen and nutrients in the tumor microenvironment (TME), which may play an important role in tumor growth and metastasis. Pancreatic neuroendocrine tumors (pNETs) are the second most common pancreatic malignancy and are frequently metastatic on presentation. Nearly a third of pNETs secrete bioactive substances causing debilitating symptoms. Current treatment options for metastatic pNETs are limited. Importantly, these tumors are highly vascularized and heterogeneous neoplasms, in which the heterogeneity of vascular endothelial cells (ECs) and de novo arteriogenesis may be critical for their progression. Current anti-angiogenetic targeted treatments have not shown substantial clinical benefits, and they are poorly tolerated. This review article describes EC heterogeneity and heterogeneous tumor-associated ECs (TAECs) in the TME and emphasizes the concept of de novo arteriogenesis in the TME. The authors also emphasize the challenges of current antiangiogenic therapy in pNETs and discuss the potential of tumor arteriogenesis as a novel therapeutic target. Finally, the authors prospect the clinical potential of targeting the FoxO1-CD36-Notch pathway that is associated with both pNET progression and arteriogenesis and provide insights into the clinical implications of targeting plasticity of cancer stem cells (CSCs) and vascular niche, particularly the arteriolar niche within the TME in pNETs, which will also provide insights into other types of cancer, including breast cancer, lung cancer, and malignant melanoma.
Collapse
Affiliation(s)
- Bin Ren
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (J.B.R.); (R.J.-S.); (C.C.); (A.B.); (H.C.)
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Nutrition & Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Diabetes Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Graduate Biomedical Science Program of the Graduate School, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Correspondence:
| | - J. Bart Rose
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (J.B.R.); (R.J.-S.); (C.C.); (A.B.); (H.C.)
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Yehe Liu
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA;
| | - Renata Jaskular-Sztul
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (J.B.R.); (R.J.-S.); (C.C.); (A.B.); (H.C.)
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Carlo Contreras
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (J.B.R.); (R.J.-S.); (C.C.); (A.B.); (H.C.)
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Adam Beck
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (J.B.R.); (R.J.-S.); (C.C.); (A.B.); (H.C.)
| | - Herbert Chen
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (J.B.R.); (R.J.-S.); (C.C.); (A.B.); (H.C.)
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Graduate Biomedical Science Program of the Graduate School, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| |
Collapse
|
|
12
|
Basic fibroblast growth factor attenuates left-ventricular remodeling following surgical ventricular restoration in a rat ischemic cardiomyopathy model. Gen Thorac Cardiovasc Surg 2019; 68:311-318. [PMID: 31410725 DOI: 10.1007/s11748-019-01187-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 08/04/2019] [Indexed: 10/26/2022]
Abstract
OBJECTIVE Although surgical ventricular restoration for ischemic cardiomyopathy is expected as an alternative or bridge to heart transplantation, post-operative remodeling of left ventricle (LV) needs to be addressed. This study aimed to examine the effect of basic fibroblast growth factor (bFGF), which induces angiogenesis and tissue regeneration in ischemic myocardium, to prevent remodeling after surgical ventricular restoration (SVR) using a rat ischemic cardiomyopathy model. METHODS Four weeks after coronary artery ligation, rats were divided into two groups: rats treated with SVR alone (SVR; n = 21), and rats treated with SVR and local sustained release of bFGF using gelatin hydrogel sheet (SVR + bFGF; n = 22). Cardiac function was assessed by serial echocardiography and cardiac catheterization. Cardiac tissue sections were histologically examined for vascular density and fibrosis. RESULTS Higher systolic function and lower LV end-diastolic pressure (LVEDP) were observed in rats treated with SVR + bFGF (SVR vs SVR + bFGF; Ees: 0.22 ± 0.11 vs 0.33 ± 0.22 mmHg/μL, p = 0.0328; LVEDP: 12.7 ± 7.0 vs 8.5 ± 4.3 mmHg, p = 0.0230). LV area tended to be lower in rats treated with SVR + bFGF compared to rats treated with SVR alone (left-ventricular end-diastolic area: 0.66 ± 0.07 vs 0.62 ± 0.07 cm2, p = 0.071). Vascular density tended to be higher in rats treated with SVR + bFGF than those without bFGF (23.3 ± 8.1 vs 28.8 ± 9.5/mm2, p = 0.0509). CONCLUSIONS BFGF induced angiogenesis and attenuated remodeling after SVR which secured the efficacy of SVR in a rat ischemic cardiomyopathy model.
Collapse
|
|
13
|
Arunkumar P, Dougherty JA, Weist J, Kumar N, Angelos MG, Powell HM, Khan M. Sustained Release of Basic Fibroblast Growth Factor (bFGF) Encapsulated Polycaprolactone (PCL) Microspheres Promote Angiogenesis In Vivo. NANOMATERIALS (BASEL, SWITZERLAND) 2019; 9:E1037. [PMID: 31330782 PMCID: PMC6669517 DOI: 10.3390/nano9071037] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 07/14/2019] [Accepted: 07/17/2019] [Indexed: 12/15/2022]
Abstract
Coronary heart disease (CHD) is the leading cause of death in the Unites States and globally. The administration of growth factors to preserve cardiac function after myocardial infarction (MI) is currently being explored. Basic fibroblast growth factor (bFGF), a potent angiogenic factor has poor clinical efficacy due to its short biological half-life and low plasma stability. The goal of this study was to develop bFGF-loaded polycaprolactone (PCL) microspheres for sustained release of bFGF and to evaluate its angiogenic potential. The bFGF-PCL microspheres (bFGF-PCL-MS) were fabricated using the emulsion solvent-evaporation method and found to have spherical morphology with a mean size of 4.21 ± 1.28 µm. In vitro bFGF release studies showed a controlled release for up to 30 days. Treatment of HUVECs with bFGF-PCL-MS in vitro enhanced their cell proliferation and migration properties when compared to the untreated control group. Treatment of HUVECs with release media from bFGF-PCL-MS also significantly increased expression of angiogenic genes (bFGF and VEGFA) as compared to untreated cells. The in vivo angiogenic potential of these bFGF-PCL-MS was further confirmed in rats using a Matrigel plug assay with subsequent immunohistochemical staining showing increased expression of angiogenic markers. Overall, bFGF-PCL-MS could serve as a potential angiogenic agent to promote cell survival and angiogenesis following an acute myocardial infarction.
Collapse
Affiliation(s)
- Pala Arunkumar
- Department of Emergency Medicine, College of Medicine, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Julie A Dougherty
- Department of Emergency Medicine, College of Medicine, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Jessica Weist
- Department of Emergency Medicine, College of Medicine, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Naresh Kumar
- Department of Emergency Medicine, College of Medicine, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Mark G Angelos
- Department of Emergency Medicine, College of Medicine, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Heather M Powell
- Department of Materials Science and Engineering, Department of Biomedical Engineering, The Ohio State University, Columbus, OH 43210, USA
- Research Department, Shriners Hospitals for Children, Cincinnati, OH 43210, USA
| | - Mahmood Khan
- Department of Emergency Medicine, College of Medicine, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
| |
Collapse
|
|
14
|
Affiliation(s)
- Ephraim Bernhard Winzer
- Department of Internal Medicine/Cardiology, Helios Stiftungsprofessur, Heart Center Leipzig-University Hospital, Leipzig, Germany
| | - Felix Woitek
- Department of Internal Medicine/Cardiology, Helios Stiftungsprofessur, Heart Center Leipzig-University Hospital, Leipzig, Germany
| | - Axel Linke
- Department of Internal Medicine and Cardiology, Technische Universität Dresden Heart Center Dresden-University Hospital, Dresden, Germany
| |
Collapse
|
|
15
|
Ziegelhoeffer T, Heil M, Fischer S, Fernández B, Schaper W, Preissner KT, Deindl E, Pagel JI. Role of early growth response 1 in arteriogenesis: Impact on vascular cell proliferation and leukocyte recruitment in vivo. Thromb Haemost 2017; 107:562-74. [DOI: 10.1160/th11-07-0490] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2011] [Accepted: 12/13/2011] [Indexed: 02/07/2023]
Abstract
SummaryBased on previous findings that early growth response 1 (Egr-1) participates in leukocyte recruitment and cell proliferation in vitro, this study was designed to investigate its mode of action during arteriogenesis in vivo. In a model of peripheral arteriogenesis, Egr-1 was significantly upregulated in growing collaterals of wild-type (WT) mice, both on mRNA and protein level. Egr-1−/− mice demonstrated delayed arteriogenesis after femoral artery ligation. They further showed increased levels of monocytes and granulocytes in the circulation, but reduced levels in adductor muscles under baseline conditions. After femoral artery ligation, elevated numbers of macrophages were detected in the perivascular zone of collaterals in Egr-1−/− mice and mRNA of leukocyte recruitment mediators was upregulated. Other Egr family members (Egr-2 to -4) were significantly upregulated only in Egr-1−/− mice, suggesting a mechanism of counterbalancing Egr-1 deficiency. Moreover, splicing factor-1, downregulated in WT mice after femoral artery ligation in the process of increased vascular cell proliferation, was upregulated in Egr-1−/− mice. αSM-actin on the other hand, significantly downregulated in WT mice, showed no differential expression in Egr-1−/− mice. While cell cycle regulator cyclin E and cdc20 were upregulated in Egr-1−/− mice, cyclin D1 expression decreased below the detection limit in collaterals, and the proliferation marker ki67 was not differentially expressed. In conclusion, compensation for deficiency in Egr-1 function in leukocyte recruitment can presumably be mediated by other transcription factors; however, Egr-1 is indispensable for effective vascular cell cycle progression in arteriogenesis.
Collapse
|
|
16
|
Zhu LP, Zhou JP, Zhang JX, Wang JY, Wang ZY, Pan M, Li LF, Li CC, Wang KK, Bai YP, Zhang GG. MiR-15b-5p Regulates Collateral Artery Formation by Targeting AKT3 (Protein Kinase B-3). Arterioscler Thromb Vasc Biol 2017; 37:957-968. [PMID: 28254819 DOI: 10.1161/atvbaha.116.308905] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Accepted: 02/16/2017] [Indexed: 11/16/2022]
Abstract
OBJECTIVE To identify circulating microRNAs that are differentially expressed in severe coronary heart disease with well or poorly developed collateral arteries and to investigate their mechanisms of action in vivo and in vitro. APPROACH AND RESULTS In our study, we identified a circulating microRNA, miR-15b-5p, with low expression that, nevertheless, characterized patients with sufficient coronary collateral artery function. Moreover, in murine hindlimb ischemia model, in situ hybridization identified that miR-15b-5p was specifically expressed in vascular endothelial cells of adductors in sham group and was remarkably downregulated after femoral artery ligation. Overexpressed miR-15b-5p significantly inhibited arteriogenesis and angiogenesis in mice. In vitro, both under basal and vascular endothelial growth factor stimulation, loss-of-function or gain-of-function studies suggested that miR-15b-5p significantly promoted or depressed the migration and proliferation of endothelial cells. We identified AKT3 (protein kinase B-3) as a direct target of miR-15b-5p. Interestingly, AKT3 deficiency by injection with Chol-AKT3-siRNA obviously suppressed arteriogenesis and the recovery of blood perfusion after femoral ligation in mice. CONCLUSIONS These results indicate that circulating miR-15b-5p is a suitable biomarker for discriminating between patients with well-developed or poorly developed collaterals. Moreover, miR-15b-5p is a key regulator of arteriogenesis and angiogenesis, which may represent a potential therapeutic target for ischemic disease.
Collapse
Affiliation(s)
- Ling-Ping Zhu
- From the Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China (L.-P.Z., J.-P.Z., J.-Y.W., Z.-Y.W., M.P., L.-F.L., L.C., G.-G.Z.); Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China (J.-X.Z., C.-C.L., Y.-P.B.); and Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China (K.-K.W.)
| | - Ji-Peng Zhou
- From the Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China (L.-P.Z., J.-P.Z., J.-Y.W., Z.-Y.W., M.P., L.-F.L., L.C., G.-G.Z.); Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China (J.-X.Z., C.-C.L., Y.-P.B.); and Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China (K.-K.W.)
| | - Jia-Xiong Zhang
- From the Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China (L.-P.Z., J.-P.Z., J.-Y.W., Z.-Y.W., M.P., L.-F.L., L.C., G.-G.Z.); Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China (J.-X.Z., C.-C.L., Y.-P.B.); and Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China (K.-K.W.)
| | - Jun-Yao Wang
- From the Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China (L.-P.Z., J.-P.Z., J.-Y.W., Z.-Y.W., M.P., L.-F.L., L.C., G.-G.Z.); Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China (J.-X.Z., C.-C.L., Y.-P.B.); and Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China (K.-K.W.)
| | - Zhen-Yu Wang
- From the Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China (L.-P.Z., J.-P.Z., J.-Y.W., Z.-Y.W., M.P., L.-F.L., L.C., G.-G.Z.); Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China (J.-X.Z., C.-C.L., Y.-P.B.); and Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China (K.-K.W.)
| | - Miao Pan
- From the Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China (L.-P.Z., J.-P.Z., J.-Y.W., Z.-Y.W., M.P., L.-F.L., L.C., G.-G.Z.); Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China (J.-X.Z., C.-C.L., Y.-P.B.); and Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China (K.-K.W.)
| | - Ling-Fang Li
- From the Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China (L.-P.Z., J.-P.Z., J.-Y.W., Z.-Y.W., M.P., L.-F.L., L.C., G.-G.Z.); Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China (J.-X.Z., C.-C.L., Y.-P.B.); and Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China (K.-K.W.)
| | - Chuan-Chang Li
- From the Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China (L.-P.Z., J.-P.Z., J.-Y.W., Z.-Y.W., M.P., L.-F.L., L.C., G.-G.Z.); Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China (J.-X.Z., C.-C.L., Y.-P.B.); and Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China (K.-K.W.)
| | - Kang-Kai Wang
- From the Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China (L.-P.Z., J.-P.Z., J.-Y.W., Z.-Y.W., M.P., L.-F.L., L.C., G.-G.Z.); Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China (J.-X.Z., C.-C.L., Y.-P.B.); and Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China (K.-K.W.)
| | - Yong-Ping Bai
- From the Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China (L.-P.Z., J.-P.Z., J.-Y.W., Z.-Y.W., M.P., L.-F.L., L.C., G.-G.Z.); Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China (J.-X.Z., C.-C.L., Y.-P.B.); and Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China (K.-K.W.)
| | - Guo-Gang Zhang
- From the Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China (L.-P.Z., J.-P.Z., J.-Y.W., Z.-Y.W., M.P., L.-F.L., L.C., G.-G.Z.); Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China (J.-X.Z., C.-C.L., Y.-P.B.); and Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China (K.-K.W.).
| |
Collapse
|
|
17
|
Association of serum mimecan with angiographic coronary collateralization in patients with stable coronary artery disease and chronic total occlusion. Atherosclerosis 2016; 252:75-81. [PMID: 27508318 DOI: 10.1016/j.atherosclerosis.2016.07.916] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Revised: 07/20/2016] [Accepted: 07/21/2016] [Indexed: 01/27/2023]
Abstract
BACKGROUND AND AIMS Mimecan/osteoglycin is identified as an emerging biomarker of coronary atherosclerosis. We investigated whether and to what extent serum mimecan reflects angiographic coronary collateralization in patients with stable coronary artery disease and chronic total occlusion. METHODS Serum levels of mimecan were determined in 559 consecutive patients with stable angina and angiographic total occlusion of at least one major coronary artery. The degree of collaterals supplying the distal aspect of a total occlusion from the contra-lateral vessel was graded as poor (Rentrop score of 0 or 1) or good coronary collateralization (Rentrop score of 2 or 3). RESULTS Serum mimecan was significantly higher in patients with poor collateralization than in those with good collateralization, and correlated inversely with Rentrop score (adjusted Spearmen's r = -0.443, p < 0.001). The prevalence of poor coronary collaterals increased stepwise from the lowest to the highest quartile of serum mimecan (OR 2.140, 95% CI 1.793-2.555; p for trend < 0.001). After adjusting for age, gender, traditional risk factors for coronary artery disease, history of myocardial infarction, severity of coronary artery disease, renal function and C-reactive protein, serum mimecan (per SD) remained an independent determinant for poor collateralization (OR 2.674, 95% CI 2.057-3.475, p < 0.001). The diagnostic value of mimecan (per SD) for detecting poor collateralization was consistent when the patients were specified by gender, age, body mass index, presence or absence of hypertension and diabetes, and status of renal function (OR 2.075-6.932, p interaction ≥ 0.059). CONCLUSION Increased serum mimecan is associated with poor angiographic coronary collateralization in patients with chronic total occlusion.
Collapse
|
|
18
|
Whiteford JR, De Rossi G, Woodfin A. Mutually Supportive Mechanisms of Inflammation and Vascular Remodeling. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2016; 326:201-78. [PMID: 27572130 DOI: 10.1016/bs.ircmb.2016.05.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Chronic inflammation is often accompanied by angiogenesis, the development of new blood vessels from existing ones. This vascular response is a response to chronic hypoxia and/or ischemia, but is also contributory to the progression of disorders including atherosclerosis, arthritis, and tumor growth. Proinflammatory and proangiogenic mediators and signaling pathways form a complex and interrelated network in these conditions, and many factors exert multiple effects. Inflammation drives angiogenesis by direct and indirect mechanisms, promoting endothelial proliferation, migration, and vessel sprouting, but also by mediating extracellular matrix remodeling and release of sequestered growth factors, and recruitment of proangiogenic leukocyte subsets. The role of inflammation in promoting angiogenesis is well documented, but by facilitating greater infiltration of leukocytes and plasma proteins into inflamed tissues, angiogenesis can also propagate chronic inflammation. This review examines the mutually supportive relationship between angiogenesis and inflammation, and considers how these interactions might be exploited to promote resolution of chronic inflammatory or angiogenic disorders.
Collapse
Affiliation(s)
- J R Whiteford
- William Harvey Research Institute, Barts and London School of Medicine and Dentistry, Queen Mary College, University of London, London, United Kingdom
| | - G De Rossi
- William Harvey Research Institute, Barts and London School of Medicine and Dentistry, Queen Mary College, University of London, London, United Kingdom
| | - A Woodfin
- Cardiovascular Division, King's College, University of London, London, United Kingdom.
| |
Collapse
|
|
19
|
Abstract
Formation of arterial vasculature, here termed arteriogenesis, is a central process in embryonic vascular development as well as in adult tissues. Although the process of capillary formation, angiogenesis, is relatively well understood, much remains to be learned about arteriogenesis. Recent discoveries point to the key role played by vascular endothelial growth factor receptor 2 in control of this process and to newly identified control circuits that dramatically influence its activity. The latter can present particularly attractive targets for a new class of therapeutic agents capable of activation of this signaling cascade in a ligand-independent manner, thereby promoting arteriogenesis in diseased tissues.
Collapse
Affiliation(s)
- Michael Simons
- From the Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine (M.S., A.E.) and Departments of Cell Biology (M.S.) and Molecular Physiology (A.E.), Yale University School of Medicine, New Haven, CT.
| | - Anne Eichmann
- From the Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine (M.S., A.E.) and Departments of Cell Biology (M.S.) and Molecular Physiology (A.E.), Yale University School of Medicine, New Haven, CT.
| |
Collapse
|
|
20
|
Dubsky M, Jirkovska A, Bem R, Fejfarova V, Varga M, Kolesar L, Pagacova L, Sykova E, Jude EB. Role of Serum Levels of Angiogenic Cytokines in Assessment of Angiogenesis after Stem Cell Therapy of Diabetic Patients with Critical Limb Ischemia. Cell Transplant 2014; 23:1517-23. [DOI: 10.3727/096368913x674071] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The release of proangiogenic cytokines into the circulation after stem cell (SC) therapy and compensatory increase of angiogenesis inhibitors may reflect local vasculogenesis but also can increase the risk of side effects. The aim of our study was to evaluate serum levels of angiogenic cytokines with regard to the assessment of local and systemic vasculogenesis in diabetic patients with no-option critical limb ischemia (NO-CLI). Twenty-five diabetic patients with NO-CLI treated with SCs isolated from bone marrow or stimulated peripheral blood were included in the study. Serum levels of proangiogenic cytokines (VEGF, bFGF, Ang-1, PDGF-AA, and PDGF-BB) and an antiangiogenic cytokine (endostatin) were assessed 6 months after cell treatment, compared to baseline values, and correlated with the number of injected CD34+ cells. The clinical effect of SC therapy (assessed by changes in TcPO2) and potential systemic vasculogenesis (assessed by eye fundus examination) were evaluated after 6 months. Serum levels of angiogenic inhibitor endostatin increased significantly after 1 and 3 months ( p = 0.0003), but no significant increase in serum levels of proangiogenic cytokines was observed. A significant correlation between number of injected CD34+ cells and serum levels of endostatin was observed ( r = 0.41, p < 0.05); however, proangiogenic cytokines did not correlate with CD34+ cells. No correlation between increase in TcPO2 after treatment and serum levels of any of the angiogenic cytokines were seen, and no signs of systemic vasculogenesis in the retina were observed after 6 months. Despite the significant increase in the levels of the angiogenic inhibitor endostatin following SC treatment, there was no risk of systemic vasculogenesis after SC therapy as documented by serum levels of proangiogenic cytokines or changes in the retina.
Collapse
Affiliation(s)
- Michal Dubsky
- Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- First Medical Faculty, Charles University, Prague, Czech Republic
| | - Alexandra Jirkovska
- Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Robert Bem
- Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Vladimira Fejfarova
- Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Martin Varga
- Clinic of Transplant Surgery, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Libor Kolesar
- Department of Immunogenetics, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Libuse Pagacova
- Autotransfusion Unit, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Eva Sykova
- Institute of Experimental Medicine, Czech Academy of Science, Prague, Czech Republic
| | - Edward. B. Jude
- Diabetes Centre, Tameside Hospital NHS Foundation Trust and University of Manchester, Ashton-Under-Lyne, Lancashire, UK
| |
Collapse
|
|
21
|
Matsumoto Y, Nakano J, Oga S, Kataoka H, Honda Y, Sakamoto J, Okita M. The non-thermal effects of pulsed ultrasound irradiation on the development of disuse muscle atrophy in rat gastrocnemius muscle. ULTRASOUND IN MEDICINE & BIOLOGY 2014; 40:1578-1586. [PMID: 24613643 DOI: 10.1016/j.ultrasmedbio.2013.12.031] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2013] [Revised: 12/10/2013] [Accepted: 12/31/2013] [Indexed: 06/03/2023]
Abstract
This study examined the effects of therapeutic pulsed ultrasound (US) on the development of disuse muscle atrophy in rat gastrocnemius muscle. Male Wistar rats were randomly distributed into control, immobilization (Im), sham US, and US groups. In the Im, sham US and US groups, the bilateral ankle joints of each rat were immobilized in full plantar flexion with a plaster cast for a 4-wk period. The pulsed US (frequency, 1 MHz; intensity, 1.0 W/cm(2); pulsed mode 1:4; 15 min) was irradiated to the gastrocnemius muscle in the US group over a 4-wk immobilization period. The pulsed US irradiation delivered only non-thermal effects to the muscle. In conjunction with US irradiation, 5-bromo-2'-deoxyuridine (BrdU) was injected subcutaneously to label the nuclei of proliferating satellite cells 1 h before each pulsed US irradiation. Immobilization resulted in significant decreases in the mean diameters of type I, IIA and IIB muscle fibers of the gastrocnemius muscle in the Im, sham US and US groups compared with the control group. However, the degrees of muscle fiber atrophy for all types were significantly lower in the US group compared with the Im and sham US groups. Although the number of capillaries and the concentrations of insulin-like growth factor and basic fibroblast growth factor did not change in the muscle, the number of BrdU-positive nuclei in the muscle was significantly increased by pulsed US irradiation in the US group. The results of this study suggest that pulsed US irradiation inhibits the development of disuse muscle atrophy partly via activation of satellite cells.
Collapse
Affiliation(s)
- Yoko Matsumoto
- Department of Rehabilitation, Saiseikai Nagasaki Hospital, Nagasaki, Japan
| | - Jiro Nakano
- Unit of Physical and Occupational Therapy, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
| | - Satoshi Oga
- Department of Rehabilitation, Saiseikai Nagasaki Hospital, Nagasaki, Japan
| | - Hideki Kataoka
- Department of Rehabilitation, Nagasaki Memorial Hospital, Nagasaki, Japan; Department of Locomotive Rehabilitation Science, Unit of Rehabilitation Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Yuichiro Honda
- Department of Locomotive Rehabilitation Science, Unit of Rehabilitation Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Junya Sakamoto
- Department of Rehabilitation, Nagasaki University Hospital, Nagasaki, Japan
| | - Minoru Okita
- Department of Locomotive Rehabilitation Science, Unit of Rehabilitation Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| |
Collapse
|
|
22
|
El polimorfismo de un solo nucleótido PLAU P141L se asocia con el grado de circulación colateral en pacientes con enfermedad arterial coronaria. Rev Esp Cardiol 2014. [DOI: 10.1016/j.recesp.2013.11.022] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
|
|
23
|
Duran J, Sánchez-Olavarría P, Mola M, Götzens V, Carballo J, Martín-Pelegrina E, Petit M, García Del Blanco B, García-Dorado D, de Anta JM. The PLAU P141L single nucleotide polymorphism is associated with collateral circulation in patients with coronary artery disease. ACTA ACUST UNITED AC 2014; 67:552-7. [PMID: 24952395 DOI: 10.1016/j.rec.2013.11.022] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Accepted: 11/13/2013] [Indexed: 11/16/2022]
Abstract
INTRODUCTION AND OBJECTIVES Urokinase-type plasminogen activator, which is encoded by the PLAU gene, plays a prominent role during collateral arterial growth. We investigated whether the PLAU P141L (C > T) polymorphism, which causes a mutation in the kringle domain of the protein, is associated with coronary collateral circulation in a cohort of 676 patients with coronary artery disease. METHODS The polymorphism was genotyped in blood samples using a TaqMan-based genotyping assay, and collateral circulation was assessed by the Rentrop method. Multivariate logistic regression models adjusted by clinically relevant variables to estimate odds ratios were used to examine associations of PLAU P141L allelic variants and genotypes with collateral circulation. RESULTS Patients with poor collateral circulation (Rentrop 0-1; n = 547) showed a higher frequency of the TT genotype than those with good collateral circulation (Rentrop 2-3; n = 129; P = .020). The T allele variant was also more common in patients with poor collateral circulation (P = .006). The odds ratio of having poorly developed collaterals in patients bearing the T allele (adjusted for clinically relevant variables) was statistically significant under the dominant model (odds ratio = 1.83 [95% confidence interval, 1.16-2.90]; P = .010) and the additive model (odds ratio = 1.73 [95% confidence interval, 1.14-2.62]; P = .009). CONCLUSIONS An association was found between coronary collateral circulation and the PLAU P141L polymorphism. Patients with the 141L variant are at greater risk of developing poor coronary collateral circulation.
Collapse
Affiliation(s)
- Joan Duran
- Unidad de Anatomía y Embriología Humanas, Departamento de Patología y Terapéutica Experimental, Facultad de Medicina, Campus de Ciencias de la Salud de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Pilar Sánchez-Olavarría
- Unidad de Anatomía y Embriología Humanas, Departamento de Patología y Terapéutica Experimental, Facultad de Medicina, Campus de Ciencias de la Salud de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain; Departamento de Estadística, Universidad de Valparaíso, Valparaíso, Chile
| | - Marina Mola
- Unidad de Anatomía y Embriología Humanas, Departamento de Patología y Terapéutica Experimental, Facultad de Medicina, Campus de Ciencias de la Salud de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain; Grupo de Investigación Neurovascular (NEUVAS), IMIM-Hospital del Mar, PRBB-Parque de Investigación Biomédica de Barcelona, Barcelona, Spain
| | - Víctor Götzens
- Unidad de Anatomía y Embriología Humanas, Departamento de Patología y Terapéutica Experimental, Facultad de Medicina, Campus de Ciencias de la Salud de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Julio Carballo
- Departamento de Cardiología y Hemodinamia, Centro Cardiovascular Sant Jordi, Barcelona, Spain
| | - Eva Martín-Pelegrina
- Departamento de Cardiología y Hemodinamia, Centro Cardiovascular Sant Jordi, Barcelona, Spain
| | - Màrius Petit
- Departamento de Cardiología y Hemodinamia, Centro Cardiovascular Sant Jordi, Barcelona, Spain
| | | | - David García-Dorado
- Departamento de Cardiología, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Josep M de Anta
- Unidad de Anatomía y Embriología Humanas, Departamento de Patología y Terapéutica Experimental, Facultad de Medicina, Campus de Ciencias de la Salud de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
| |
Collapse
|
|
24
|
Silvestre JS, Smadja DM, Lévy BI. Postischemic revascularization: from cellular and molecular mechanisms to clinical applications. Physiol Rev 2013; 93:1743-802. [PMID: 24137021 DOI: 10.1152/physrev.00006.2013] [Citation(s) in RCA: 181] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
After the onset of ischemia, cardiac or skeletal muscle undergoes a continuum of molecular, cellular, and extracellular responses that determine the function and the remodeling of the ischemic tissue. Hypoxia-related pathways, immunoinflammatory balance, circulating or local vascular progenitor cells, as well as changes in hemodynamical forces within vascular wall trigger all the processes regulating vascular homeostasis, including vasculogenesis, angiogenesis, arteriogenesis, and collateral growth, which act in concert to establish a functional vascular network in ischemic zones. In patients with ischemic diseases, most of the cellular (mainly those involving bone marrow-derived cells and local stem/progenitor cells) and molecular mechanisms involved in the activation of vessel growth and vascular remodeling are markedly impaired by the deleterious microenvironment characterized by fibrosis, inflammation, hypoperfusion, and inhibition of endogenous angiogenic and regenerative programs. Furthermore, cardiovascular risk factors, including diabetes, hypercholesterolemia, hypertension, diabetes, and aging, constitute a deleterious macroenvironment that participates to the abrogation of postischemic revascularization and tissue regeneration observed in these patient populations. Thus stimulation of vessel growth and/or remodeling has emerged as a new therapeutic option in patients with ischemic diseases. Many strategies of therapeutic revascularization, based on the administration of growth factors or stem/progenitor cells from diverse sources, have been proposed and are currently tested in patients with peripheral arterial disease or cardiac diseases. This review provides an overview from our current knowledge regarding molecular and cellular mechanisms involved in postischemic revascularization, as well as advances in the clinical application of such strategies of therapeutic revascularization.
Collapse
|
|
25
|
Local delivery of polarized macrophages improves reperfusion recovery in a mouse hind limb ischemia model. PLoS One 2013; 8:e68811. [PMID: 23894348 PMCID: PMC3722193 DOI: 10.1371/journal.pone.0068811] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2013] [Accepted: 05/31/2013] [Indexed: 12/31/2022] Open
Abstract
AIMS Enhancement of collateral development in coronary or peripheral artery disease is a therapeutic target, but it has proven difficult to achieve. Macrophages are key players in collateral remodeling, yet the effect of different macrophage subsets on arteriogenesis has not been investigated. METHODS AND RESULTS Murine macrophages were cultured from bone marrow and polarized into M1 (IFNγ), M2a (IL-4) or M2c (IL-10) subsets. C57BL/6 mice underwent femoral artery ligation followed by intramuscular injection of macrophage subsets. Using eGFP expressing macrophages, cells could be detected at least 6 days after ligation and were located in the perivascular space of collateral vessels. After 14 days, perfusion ratio was increased in animals treated with M1 as well as M2a and M2c macrophages compared to control. Depletion of circulating monocytes by clodronate liposome injections did not hamper reperfusion recovery, however, treatment with exogenous polarized macrophages improved perfusion ratio after 14 days again. We used IL10R(fl/fl)/LysMCre(+) mice to study the effect of inhibition of endogenous polarization towards specifically M2c macrophages on arteriogenesis. Deletion of the IL10-receptor (IL10R) in the myeloid lineage did not affect reperfusion recovery, yet the pro-arteriogenic effect of exogenously injected M2c macrophages was still present. CONCLUSIONS Local injection of polarized macrophages promotes reperfusion recovery after femoral artery ligation and is not influenced by depletion of circulatory monocytes. Preventing endogenous M2c polarization did not affect reperfusion recovery suggesting that M2c's are not required for collateralization, but are sufficient to induce collateral formation upon exogenous administration. This is the first study using local injection of macrophage subsets showing the pro-arteriogenic effect of polarized macrophages.
Collapse
|
|
26
|
Jazwa A, Tomczyk M, Taha HM, Hytonen E, Stoszko M, Zentilin L, Giacca M, Yla-Herttuala S, Emanueli C, Jozkowicz A, Dulak J. Arteriogenic therapy based on simultaneous delivery of VEGF-A and FGF4 genes improves the recovery from acute limb ischemia. Vasc Cell 2013; 5:13. [PMID: 23816205 PMCID: PMC3703285 DOI: 10.1186/2045-824x-5-13] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2012] [Accepted: 06/14/2013] [Indexed: 01/12/2023] Open
Abstract
Background Gene therapy stimulating the growth of blood vessels is considered for the treatment of peripheral and myocardial ischemia. Here we aimed to achieve angiogenic synergism between vascular endothelial growth factor-A (VEGF-A, VEGF) and fibroblast growth factor 4 (FGF4) in murine normoperfused and ischemic limb muscles. Methods Adeno-associated viral vectors (AAVs) carrying β-galactosidase gene (AAV-LacZ), VEGF-A (AAV-VEGF-A) or two angiogenic genes (AAV-FGF4-IRES-VEGF-A) were injected into the normo-perfused adductor muscles of C57Bl/6 mice. Moreover, in a different experiment, mice were subjected to unilateral hindlimb ischemia by femoral artery ligation followed by intramuscular injections of AAV-LacZ, AAV-VEGF-A or AAV-FGF4-IRES-VEGF-A below the site of ligation. Post-ischemic blood flow recovery was assessed sequentially by color laser Doppler. Mice were monitored for 28 days. Results VEGF-A delivered alone (AAV-VEGF-A) or in combination with FGF4 (AAV-FGF4-IRES-VEGF-A) increased the number of capillaries in normo-perfused hindlimbs when compared to AAV-LacZ. Simultaneous overexpression of both agents (VEGF-A and FGF4) stimulated the capillary wall remodeling in the non-ischemic model. Moreover, AAV-FGF4-IRES-VEGF-A faster restored the post-ischemic foot blood flow and decreased the incidence of toe necrosis in comparison to AAV-LacZ. Conclusions Synergy between VEGF-A and FGF4 to produce stable and functional blood vessels may be considered a promising option in cardiovascular gene therapy.
Collapse
Affiliation(s)
- Agnieszka Jazwa
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland
| | - Mateusz Tomczyk
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland
| | - Hevidar M Taha
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland
| | - Elisa Hytonen
- Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Mateusz Stoszko
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland
| | - Lorena Zentilin
- Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
| | - Mauro Giacca
- Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
| | - Seppo Yla-Herttuala
- Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Costanza Emanueli
- Laboratory of Vascular Pathology and Regeneration, School of Clinical Sciences, Regenerative Medicine Section, University of Bristol, Bristol, UK
| | - Alicja Jozkowicz
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland
| | - Jozef Dulak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland
| |
Collapse
|
|
27
|
Böring YC, Flögel U, Jacoby C, Heil M, Schaper W, Schrader J. Lack of ecto-5'-nucleotidase (CD73) promotes arteriogenesis. Cardiovasc Res 2012; 97:88-96. [PMID: 22977005 DOI: 10.1093/cvr/cvs286] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
AIMS Adenosine can stimulate angiogenesis, but its role in the distinct process of arteriogenesis is unknown. We have previously reported that mice lacking ecto-5'-nucleotidase (CD73-/-) show enhanced monocyte adhesion to the endothelium after ischaemia, which is considered to be an important trigger for arteriogenesis. METHODS AND RESULTS Hindlimb ischaemia was induced in wild-type (WT) and CD73-/- mice to study the role of extracellularly formed adenosine in arteriogenesis. Magnetic resonance angiography (MRA) was performed for serial visualization of newly developed vessels at a spatial resolution of 1 nL, and high-energy phosphates (HEP) were quantified by (31)P MR spectroscopy (MRS). MRA of CD73-/- mice revealed substantially enhanced collateral artery conductance at day 7 [CD73-/-: 0.73 ± 0.11 a.u. (arbitrary units); WT: 0.44 ± 0.13 a.u.; P < 0.01, n = 6], and MRS of the affected hindlimb showed a faster restoration of HEP in correlation with enhanced functional recovery in the mutant. Additionally, histology showed no differences in capillary density between the groups but showed an increased monocyte infiltration in hindlimbs of CD73-/- mice. CONCLUSION Serial assessment of dynamic changes of vessel growth and metabolism in the process of arteriogenesis demonstrate that the lack of CD73-derived adenosine importantly promotes arteriogenesis but does not alter angiogenesis in our model of hindlimb ischaemia.
Collapse
Affiliation(s)
- Yang Chul Böring
- Department of Molecular Cardiology, Heinrich Heine University of Düsseldorf, Moorenstr. 5, Düsseldorf 40225, Germany
| | | | | | | | | | | |
Collapse
|
|
28
|
Murakami M, Sakurai T. Role of fibroblast growth factor signaling in vascular formation and maintenance: orchestrating signaling networks as an integrated system. WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE 2012; 4:615-29. [PMID: 22930472 DOI: 10.1002/wsbm.1190] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The vascular system has begun to be perceived as a dynamic organ actively controlling a wide variety of physiological processes. The structural and functional integrity of blood vessels, regulated by signaling activities finely modulating cell-cell and cell-matrix interactions, is crucial for vessel physiology, as well as basic functionality of the tissue. Throughout the process of new vessel formation, while blood vessels are actively reorganized and remodeled with migration and proliferation of vascular cells, maintenance of vascular barrier function is essentially important. These conflicting properties, i.e., dynamic cellular mobilization and maintenance of barrier integrity, are simultaneously achieved through the interaction of highly organized signaling networks governing coordinated cell-cell interplay. Recent evidence suggests that the fibroblast growth factor (FGF) system plays a regulatory role in several physiological conditions in the vascular system. In this article, we will attempt to summarize current knowledge in order to understand the mechanism of this coordination and evaluate the pivotal role of FGF signaling in integrating a diverse range of signaling events in vascular growth and maintenance.
Collapse
Affiliation(s)
- Masahiro Murakami
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, USA.
| | | |
Collapse
|
|
29
|
Regulation of collateral blood vessel development by the innate and adaptive immune system. Trends Mol Med 2012; 18:494-501. [PMID: 22818027 DOI: 10.1016/j.molmed.2012.06.007] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2012] [Revised: 05/11/2012] [Accepted: 06/15/2012] [Indexed: 12/21/2022]
|
|
30
|
Rocic P. Why is coronary collateral growth impaired in type II diabetes and the metabolic syndrome? Vascul Pharmacol 2012; 57:179-86. [PMID: 22342811 DOI: 10.1016/j.vph.2012.02.001] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2011] [Revised: 01/30/2012] [Accepted: 02/01/2012] [Indexed: 11/26/2022]
Abstract
Type II diabetes and the metabolic syndrome are strong predictors of severity of occlusive coronary disease and poorer outcomes of coronary revascularization therapies. Coronary collateral growth can provide an alternative or accessory pathway of revascularization. However, collateral growth is impaired in type II diabetes and the metabolic syndrome. Although many factors necessary for collateral growth are known and many interventions have shown promising results in animal studies, not a single attempt to induce coronary collateral growth in human clinical trials has led to satisfactory results. Accordingly, the first part of this review outlines the known deleterious effects of diabetes and the metabolic syndrome on factors necessary for collateral growth, including pro-angiogenic growth factors, endothelial function, the redox state of the coronary circulation, intracellular signaling, leukocytes and bone marrow-derived progenitors cells. The second section highlights the gaps in our current knowledge of how these factors interact with the radically altered environment of the coronary circulation in diabetes and the metabolic syndrome. The interplay between these pathologies and inadequately explored areas related to the temporal regulation of collateral remodeling and the roles of the extracellular matrix, vascular cell phenotype and pro-inflammatory cytokines are emphasized with implications to development of efficient therapies.
Collapse
Affiliation(s)
- Petra Rocic
- Department of Biochemistry and Molecular Biology, University of South Alabama College of Medicine, Mobile, AL 36688, United States.
| |
Collapse
|
|
31
|
Pöling J, Szibor M, Schimanski S, Ingelmann ME, Rees W, Gajawada P, Kochfar Z, Lörchner H, Salwig I, Shin JY, Wiebe K, Kubin T, Warnecke H, Braun T. Induction of Smooth Muscle Cell Migration During Arteriogenesis Is Mediated by Rap2. Arterioscler Thromb Vasc Biol 2011; 31:2297-305. [DOI: 10.1161/atvbaha.111.232835] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Objective—
Collateral artery growth or arteriogenesis is the primary means of the circulatory system to maintain blood flow in the face of major arterial occlusions. Arteriogenesis depends on activation of fibroblast growth factor (FGF) receptors, but relatively little is known about downstream mediators of FGF signaling.
Methods and Results—
We screened for signaling components that are activated in response to administration of FGF-2 to cultured vascular smooth muscle cells (VSMCs) and detected a significant increase of Rap2 but not of other Ras family members, which corresponded to a strong upregulation of Rap2 and C-Raf in growing collaterals from rabbits with femoral artery occlusion. Small interfering RNAs directed against Rap2 did not affect FGF-2 induced proliferation of VSMC but strongly inhibited their migration. Inhibition of FGF receptor-1 (FGFR1) signaling by infusion of a sulfonic acid polymer or infection with a dominant-negative FGFR1 adenovirus inhibited Rap2 upregulation and collateral vessel growth. Similarly, expression of dominant-negative Rap2 blocked arteriogenesis, whereas constitutive active Rap2 enhanced collateral vessel growth.
Conclusion—
Rap2 is part of the arteriogenic program and acts downstream of the FGFR1 to stimulate VSMC migration. Specific modulation of Rap2 might be an attractive target to manipulate VSMC migration, which plays a role in numerous pathological processes.
Collapse
Affiliation(s)
- Jochen Pöling
- From the Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (J.P., M.S., S.S., M.-E.I., P.G., Z.K., H.L., I.S., J.-Y.S., T.K., T.B.); Department of Cardiac Surgery, Schüchtermann-Klinik, Bad Rothenfelde, Germany (J.P., W.R., H.W.); University Hospital Münster, Germany (K.W.)
| | - Marten Szibor
- From the Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (J.P., M.S., S.S., M.-E.I., P.G., Z.K., H.L., I.S., J.-Y.S., T.K., T.B.); Department of Cardiac Surgery, Schüchtermann-Klinik, Bad Rothenfelde, Germany (J.P., W.R., H.W.); University Hospital Münster, Germany (K.W.)
| | - Silvia Schimanski
- From the Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (J.P., M.S., S.S., M.-E.I., P.G., Z.K., H.L., I.S., J.-Y.S., T.K., T.B.); Department of Cardiac Surgery, Schüchtermann-Klinik, Bad Rothenfelde, Germany (J.P., W.R., H.W.); University Hospital Münster, Germany (K.W.)
| | - Marie-Elisabeth Ingelmann
- From the Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (J.P., M.S., S.S., M.-E.I., P.G., Z.K., H.L., I.S., J.-Y.S., T.K., T.B.); Department of Cardiac Surgery, Schüchtermann-Klinik, Bad Rothenfelde, Germany (J.P., W.R., H.W.); University Hospital Münster, Germany (K.W.)
| | - Wolfgang Rees
- From the Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (J.P., M.S., S.S., M.-E.I., P.G., Z.K., H.L., I.S., J.-Y.S., T.K., T.B.); Department of Cardiac Surgery, Schüchtermann-Klinik, Bad Rothenfelde, Germany (J.P., W.R., H.W.); University Hospital Münster, Germany (K.W.)
| | - Praveen Gajawada
- From the Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (J.P., M.S., S.S., M.-E.I., P.G., Z.K., H.L., I.S., J.-Y.S., T.K., T.B.); Department of Cardiac Surgery, Schüchtermann-Klinik, Bad Rothenfelde, Germany (J.P., W.R., H.W.); University Hospital Münster, Germany (K.W.)
| | - Zaber Kochfar
- From the Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (J.P., M.S., S.S., M.-E.I., P.G., Z.K., H.L., I.S., J.-Y.S., T.K., T.B.); Department of Cardiac Surgery, Schüchtermann-Klinik, Bad Rothenfelde, Germany (J.P., W.R., H.W.); University Hospital Münster, Germany (K.W.)
| | - Holger Lörchner
- From the Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (J.P., M.S., S.S., M.-E.I., P.G., Z.K., H.L., I.S., J.-Y.S., T.K., T.B.); Department of Cardiac Surgery, Schüchtermann-Klinik, Bad Rothenfelde, Germany (J.P., W.R., H.W.); University Hospital Münster, Germany (K.W.)
| | - Isabelle Salwig
- From the Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (J.P., M.S., S.S., M.-E.I., P.G., Z.K., H.L., I.S., J.-Y.S., T.K., T.B.); Department of Cardiac Surgery, Schüchtermann-Klinik, Bad Rothenfelde, Germany (J.P., W.R., H.W.); University Hospital Münster, Germany (K.W.)
| | - Jae-Young Shin
- From the Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (J.P., M.S., S.S., M.-E.I., P.G., Z.K., H.L., I.S., J.-Y.S., T.K., T.B.); Department of Cardiac Surgery, Schüchtermann-Klinik, Bad Rothenfelde, Germany (J.P., W.R., H.W.); University Hospital Münster, Germany (K.W.)
| | - Karsten Wiebe
- From the Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (J.P., M.S., S.S., M.-E.I., P.G., Z.K., H.L., I.S., J.-Y.S., T.K., T.B.); Department of Cardiac Surgery, Schüchtermann-Klinik, Bad Rothenfelde, Germany (J.P., W.R., H.W.); University Hospital Münster, Germany (K.W.)
| | - Thomas Kubin
- From the Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (J.P., M.S., S.S., M.-E.I., P.G., Z.K., H.L., I.S., J.-Y.S., T.K., T.B.); Department of Cardiac Surgery, Schüchtermann-Klinik, Bad Rothenfelde, Germany (J.P., W.R., H.W.); University Hospital Münster, Germany (K.W.)
| | - Henning Warnecke
- From the Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (J.P., M.S., S.S., M.-E.I., P.G., Z.K., H.L., I.S., J.-Y.S., T.K., T.B.); Department of Cardiac Surgery, Schüchtermann-Klinik, Bad Rothenfelde, Germany (J.P., W.R., H.W.); University Hospital Münster, Germany (K.W.)
| | - Thomas Braun
- From the Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (J.P., M.S., S.S., M.-E.I., P.G., Z.K., H.L., I.S., J.-Y.S., T.K., T.B.); Department of Cardiac Surgery, Schüchtermann-Klinik, Bad Rothenfelde, Germany (J.P., W.R., H.W.); University Hospital Münster, Germany (K.W.)
| |
Collapse
|
|
32
|
Matsuse D, Kitada M, Ogura F, Wakao S, Kohama M, Kira JI, Tabata Y, Dezawa M. Combined transplantation of bone marrow stromal cell-derived neural progenitor cells with a collagen sponge and basic fibroblast growth factor releasing microspheres enhances recovery after cerebral ischemia in rats. Tissue Eng Part A 2011; 17:1993-2004. [PMID: 21457094 DOI: 10.1089/ten.tea.2010.0585] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Bone marrow stromal cells (MSCs) are a useful source of cells because of their abundant supply and few associated ethical problems. We have previously reported that neural progenitor cells (NS-MSCs) can be effectively induced from MSCs and differentiate into neurons to contribute to functional recovery when transplanted into the rat stroke model. In this study, we attempted to enhance the therapeutic effects of NS-MSCs with a collagen sponge and basic fibroblast growth factor (bFGF) releasing microspheres. NS-MSCs were generated from MSCs by transfection of Notch-1 intracellular domain followed by culturing the cells in a free-floating culture system. The resulting NS-MSCs were transplanted into the rats with induced brain ischemia by using collagen sponges as scaffolds for transplanted cells, and with bFGF incorporated into gelatin microspheres to aid neovascularization around the transplanted region and proliferation of neural stem cells/neural progenitor cells. In culture, NS-MSCs successfully formed spheres containing cells highly expressing neural progenitor markers. Cell survival, neovascularization, and proliferation of host neural stem cells/neural progenitor cells were improved in animals that received NS-MSCs together with these biomaterials. Behavioral analysis also revealed significant functional recovery. These observations demonstrate that transplantation of NS-MSCs in combination with a collagen sponge and bFGF releasing microspheres significantly improves histological and functional recovery in the rat stroke model. When used with these biomaterials, NS-MSCs would be a promising cell source for treating stroke and neurodegenerative diseases.
Collapse
Affiliation(s)
- Dai Matsuse
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Yu C, Wang J, Fu Y, Mao Y, Chen Y, Jiang Y, Liao X, Guo J, Xu Q, Li J. Treatment of skin injury due to vinorelbine extravasation using bFGF and rhGM-CSF: an experimental study in a murine model. Biol Res Nurs 2010; 13:32-7. [PMID: 20798155 DOI: 10.1177/1099800410378160] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND OBJECTIVE A murine model of skin injury from vinorelbine extravasation was established to evaluate the treatment efficacy of basic fibroblast growth factor (bFGF) and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF). MATERIALS AND METHOD Experimental models were divided into bFGF, rhGM-CSF, and control (saline) groups, with 40 mice in each group. Edema and ulceration were measured on Days 1, 3, 5, 7, 10, 14, and 18 after the onset of extravasation; injuries were examined pathomorphologically in three mice/group/time point. RESULTS Edema reached maximum size on Day 3 in the bFGF and rhGM-CSF groups and Day 5 in the control group. The difference between the two experimental groups was not significant; differences between the control group and the experimental groups were statistically significant at all time points. Edema and ulceration began to improve on Day 10 in the bFGF and rhGM-CSF groups and Day 18 in the control group. Healing duration was 14-18 days in the experimental groups, with a (not significantly) shorter duration in the bFGF group. Healing was completed by Day 27.5 in the control group. Pathomorphological evaluation showed regular re-epithelization and newly formed granulation tissue in the bFGF and rhGM-CSF groups on Day 13. In the control group, wounds were partially healed, edema and shallow ulcers existed, and epithelization was fragile and disorganized on Day 18. CONCLUSIONS bFGF and rhGM-CSF are useful for the treatment of skin injury due to vinorelbine extravasation, but bFGF may be slightly more effective in decreasing time and improving quality of healing.
Collapse
Affiliation(s)
- Chunhua Yu
- Division of Thoracic Oncology, West China Hospital, West China School of Clinical Medicine, Sichuan University, Chengdu, China
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
34
|
Zhao Y, Liu Z, Pan C, Li Z, Zhou J, Wang J, Yin Z, Wang X. Preparation of gelatin microspheres encapsulated with bFGF for therapeutic angiogenesis in a canine ischemic hind limb. JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION 2010; 22:665-82. [PMID: 20566051 DOI: 10.1163/092050610x489880] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
There is urgent need for the treatment of limb ischemia. In order to avoid the risk of genetic materials or injury in collection of implanted cells, a basic fibroblast growth factor (bFGF) sustained release system using cross-linked gelatin microspheres was developed for therapeutic angiogenesis. In this study, gelatin microspheres (MSs) and the complex of MSs and bFGF (MSs-bFGF) were prepared. MSs and MSs-bFGF were analyzed for morphology, particle size, in vitro bFGF release and the bioactivity of the released medium. MSs-bFGF was intramuscularly implanted into the ischemic hind limb of a dog and free bFGF, empty MSs and untreated animals were used as controls. Histological examination was performed for angiogenesis evaluation. After immersion in an aqueous solution, the un-cross-linked MSs became deformed and adhered together. The cross-linked MSs showed a more stable character both in vivo and in vitro. The bFGF released from MSs remained bioactive. The histological examination indicated that the densities of micro-vessels in the MSs-bFGF-treated hind limb muscle were significantly greater than that in the untreated control, free bFGF and empty MSs groups. The MSs-bFGF sustained release system was a simple, safe and effective way to achieve therapeutic angiogenesis in an ischemic limb.
Collapse
Affiliation(s)
- Yilin Zhao
- Department of Vascular Surgery, Zhongshan Hospital, Xiamen University, Xiamen, PR China
| | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Immunohistochemical study of the growth factors, aFGF, bFGF, PDGF-AB, VEGF-A and its receptor (Flk-1) during arteriogenesis. Mol Cell Biochem 2010; 343:223-9. [PMID: 20559689 DOI: 10.1007/s11010-010-0517-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2010] [Accepted: 06/05/2010] [Indexed: 12/13/2022]
Abstract
Growth factors are viewed as main arteriogenic stimulators for collateral vessel growth. However, the information about their native expression and distribution in collateral vessels is still limited. This study was designed to profile expression of acidic and basic FGF, platelet-derived growth factor (PDGF-AB) and vascular endothelial growth factor (VEGF-A) and its receptor, fetal liver kinase-1 (Flk-1) during arteriogenesis by confocal immunofluorescence in both dog ameroid constrictor model and rabbit arteriovenous shunt model of arteriogenesis. We found that: (1) in normal arteries (NA) in dog heart, aFGF, bFGF, and PDGF-AB all were mainly expressed in endothelial cells (EC) and media smooth muscle cells (SMC), but the expression of aFGF was very weak, with those of the other two being moderate; (2) in collateral arteries (CAs), aFGF, bFGF, and PDGF-AB all were significantly upregulated (P < 0.05); they were present in all the layers of the vascular wall and were 2.1, 1.7, and 1.9 times higher than that in NA, respectively; and (3) in NA in rabbit hind limb, VEGF-A was absent, Flk-1 was only weakly present in endothelial cells, but in one week CAs VEGF-A and Flk-1 were significantly increased in both shunt and ligation sides; this was more evident in the shunt-side CAs, 2.3, and 2 times higher than that in the ligation side, respectively. In conclusion, our data demonstrate for the first time that growth factors, aFGF, bFGF, and PDGF-AB are significantly upregulated in collateral vessels in dog heart, and enhanced VEGF-A and its receptor, Flk-1, are associated with rapid and lasting increased shear stress. These findings suggest that endogenous production of growth factors could be an important factor promoting collateral vessel growth.
Collapse
|
|
36
|
Fujii Y, Soga J, Nakamura S, Hidaka T, Hata T, Idei N, Fujimura N, Nishioka K, Chayama K, Kihara Y, Higashi Y. Classification of Corkscrew Collaterals in Thromboangiitis Obliterans (Buerger's Disease) - Relationship Between Corkscrew Type and Prevalence of Ischemic Ulcers -. Circ J 2010; 74:1684-8. [DOI: 10.1253/circj.cj-09-0878] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Yuichi Fujii
- Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical Sciences
| | - Junko Soga
- Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical Sciences
| | - Shuji Nakamura
- Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical Sciences
| | - Takayuki Hidaka
- Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical Sciences
| | - Takaki Hata
- Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical Sciences
| | - Naomi Idei
- Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical Sciences
| | - Noritaka Fujimura
- Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical Sciences
| | - Kenji Nishioka
- Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical Sciences
| | - Kazuaki Chayama
- Department of Medicine and Molecular Science, Hiroshima University Graduate School of Biomedical Sciences
| | - Yasuki Kihara
- Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical Sciences
| | - Yukihito Higashi
- Department of Cardiovascular Physiology and Medicine, Hiroshima University Graduate School of Biomedical Sciences
| |
Collapse
|
|
37
|
Finetti F, Donnini S, Giachetti A, Morbidelli L, Ziche M. Prostaglandin E(2) primes the angiogenic switch via a synergic interaction with the fibroblast growth factor-2 pathway. Circ Res 2009; 105:657-66. [PMID: 19713533 DOI: 10.1161/circresaha.109.203760] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
RATIONALE Prostaglandin (PG)E(2) exerts temporally distinct actions on blood vessels, immediate vasodilatation, and long-term activation of angiogenesis. OBJECTIVE To study the mechanism of PGE(2) induction of angiogenesis, we characterized its effect on fibroblast growth factor (FGF)-2 signaling in cultured endothelial cells and in ex vivo and in vivo assays of blood vessel formation. METHODS AND RESULTS Using Western blotting assay, we demonstrated that PGE(2) induced upregulation of components of the FGF-2 pathway: FGF-2 protein, phosphorylation of FGF receptor type 1 (FGFR1), activation of FRS2alpha (FGFR substrate 2alpha), phospholipase Cgamma, endothelial nitric oxide synthase, extracellular signal-regulated kinase 1/2, and the transcription factor STAT-3. Synergism between PGE(2) and FGF-2 promoted endothelial cell proliferation and robust angiogenesis in vivo, in rabbit cornea and Matrigel assays. The magnitude of the angiogenic response to PGE(2) was directly related to FGF-2 availability which determined the extent of FGFR1 activation. In fact, PGE(2) induction of angiogenesis in vitro was impaired in FGF-2(-/-) endothelial cells and FGFR1 blockade abrogated PGE(2) action on the endothelium, preventing the activation of FGF-2 signaling. CONCLUSION We propose a model for the angiogenic switch based on the autocrine/paracrine FGF-2/FGFR1 activation by PGE(2) and FGF-2 synergistic interaction. The synergism between the PGE(2) and FGF-2 signaling pathways here described may explain the mechanism of action of drug combinations, the most notable being cyclooxygenase inhibitors with growth factors or growth factor receptor inhibitors.
Collapse
Affiliation(s)
- Federica Finetti
- Department of Molecular Biology, University of Siena, and Istituto Toscano Tumori, Italy
| | | | | | | | | |
Collapse
|
|
38
|
Takayama T, Taguchi T, Koyama H, Sakari M, Kamimura W, Takato T, Miyata T, Nagawa H. The growth of a vascular network inside a collagen–citric acid derivative hydrogel in rats. Biomaterials 2009; 30:3580-7. [PMID: 19362365 DOI: 10.1016/j.biomaterials.2009.03.026] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2008] [Accepted: 03/17/2009] [Indexed: 11/26/2022]
|
|
39
|
Hashimoto T, Koyama H, Miyata T, Hosaka A, Tabata Y, Takato T, Nagawa H. Selective and sustained delivery of basic fibroblast growth factor (bFGF) for treatment of peripheral arterial disease: results of a phase I trial. Eur J Vasc Endovasc Surg 2009; 38:71-5. [PMID: 19328029 DOI: 10.1016/j.ejvs.2009.02.005] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2008] [Accepted: 02/17/2009] [Indexed: 12/21/2022]
Abstract
OBJECTIVES The aim of this study was to evaluate the safety of selective and sustained delivery of basic fibroblast growth factor (bFGF) using acidic gelatine hydrogel microspheres (AGHMs) for the treatment of peripheral arterial disease (PAD). MATERIALS AND METHODS We conducted a non-randomised and uncontrolled trial involving prospective observation of eight patients (eight limbs) with PAD - five limbs with arteriosclerosis obliterans and three limbs with thromboangiitis obliterans, five limbs (three arms and two legs) with critical limb ischaemia (CLI) and three limbs with intermittent claudication (IC) - who were followed up for 6 months or more. AGHM suspension containing 100 microg bFGF was infused into the artery of the affected limb. Besides evaluation of safety and changes in symptoms, resting ankle-brachial pressure index measurement and transcutaneous PO(2) (tcPO(2)), angiography were conducted at baseline and then at various time points. Skin perfusion pressure as an index of CLI and claudication distance as an index of IC were also used to assess clinical improvement and limb perfusion. RESULTS No serious adverse events were observed. All cases showed improvement in symptoms, although this was temporary in some patients. CONCLUSION Selective delivery of bFGF using AGHMs was suggested to be safe and well-tolerated in patients with PAD.
Collapse
Affiliation(s)
- T Hashimoto
- Division of Vascular Surgery, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | | | | | | | | | | | | |
Collapse
|
|
40
|
Pinkenburg O, Pfosser A, Hinkel R, Böttcher M, Dinges C, Lebherz C, Sultana S, Enssle J, El-Aouni C, Büning H, Boekstegers P, Bals R, Kupatt C. Recombinant Adeno-Associated Virus-Based Gene Transfer of Cathelicidin Induces Therapeutic Neovascularization Preferentially via Potent Collateral Growth. Hum Gene Ther 2009; 20:159-67. [DOI: 10.1089/hum.2007.178] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Affiliation(s)
- Olaf Pinkenburg
- Division of Pulmonology, Department of Internal Medicine, Hospital of the University of Marburg, Philipps Universität Marburg, 35043 Marburg, Germany
| | - Achim Pfosser
- Internal Medicine I, University Clinic Munich-Grosshadern, Ludwig Maximilians University, 81377 Munich, Germany
| | - Rabea Hinkel
- Internal Medicine I, University Clinic Munich-Grosshadern, Ludwig Maximilians University, 81377 Munich, Germany
| | - Martina Böttcher
- Internal Medicine I, University Clinic Munich-Grosshadern, Ludwig Maximilians University, 81377 Munich, Germany
| | - Claudia Dinges
- Internal Medicine I, University Clinic Munich-Grosshadern, Ludwig Maximilians University, 81377 Munich, Germany
| | - Corinna Lebherz
- Internal Medicine I, University Clinic Munich-Grosshadern, Ludwig Maximilians University, 81377 Munich, Germany
| | - Shahana Sultana
- Internal Medicine I, University Clinic Munich-Grosshadern, Ludwig Maximilians University, 81377 Munich, Germany
| | - Jörg Enssle
- Hämatologicum, Institute for Molecular Immunology, Forschungszentrum für Gesundheit und Umwelt (GSF), 81377 Munich, Germany
| | - Chiraz El-Aouni
- Internal Medicine I, University Clinic Munich-Grosshadern, Ludwig Maximilians University, 81377 Munich, Germany
| | - Hildegard Büning
- Clinic I for Internal Medicine and Center for Molecular Medicine, University of Cologne, 50937 Cologne, Germany
| | - Peter Boekstegers
- Internal Medicine I, University Clinic Munich-Grosshadern, Ludwig Maximilians University, 81377 Munich, Germany
| | - Robert Bals
- Division of Pulmonology, Department of Internal Medicine, Hospital of the University of Marburg, Philipps Universität Marburg, 35043 Marburg, Germany
| | - Christian Kupatt
- Internal Medicine I, University Clinic Munich-Grosshadern, Ludwig Maximilians University, 81377 Munich, Germany
| |
Collapse
|
|
41
|
Abstract
Following an arterial occlusion outward remodeling of pre-existent inter-connecting arterioles occurs by proliferation of vascular smooth muscle and endothelial cells. This is initiated by deformation of the endothelial cells through increased pulsatile fluid shear stress (FSS) caused by the steep pressure gradient between the high pre-occlusive and the very low post-occlusive pressure regions that are interconnected by collateral vessels. Shear stress leads to the activation and expression of all NOS isoforms and NO production, followed by endothelial VEGF secretion, which induces MCP-1 synthesis in endothelium and in the smooth muscle of the media. This leads to attraction and activation of monocytes and T-cells into the adventitial space (peripheral collateral vessels) or attachment of these cells to the endothelium (coronary collaterals). Mononuclear cells produce proteases and growth factors to digest the extra-cellular scaffold and allow motility and provide space for the new cells. They also produce NO from iNOS, which is essential for arteriogenesis. The bulk of new tissue production is carried by the smooth muscles of the media, which transform their phenotype from a contractile into a synthetic and proliferative one. Important roles are played by actin binding proteins like ABRA, cofilin, and thymosin beta 4 which determine actin polymerization and maturation. Integrins and connexins are markedly up-regulated. A key role in this concerted action which leads to a 2-to-20 fold increase in vascular diameter, depending on species size (mouse versus human) are the transcription factors AP-1, egr-1, carp, ets, by the Rho pathway and by the Mitogen Activated Kinases ERK-1 and -2. In spite of the enormous increase in tissue mass (up to 50-fold) the degree of functional restoration of blood flow capacity is incomplete and ends at 30% of maximal conductance (coronary) and 40% in the vascular periphery. The process of arteriogenesis can be drastically stimulated by increases in FSS (arterio-venous fistulas) and can be completely blocked by inhibition of NO production, by pharmacological blockade of VEGF-A and by the inhibition of the Rho-pathway. Pharmacological stimulation of arteriogenesis, important for the treatment of arterial occlusive diseases, seems feasible with NO donors.
Collapse
|
|
42
|
The proteoglycan osteoglycin/mimecan is correlated with arteriogenesis. Mol Cell Biochem 2008; 322:15-23. [PMID: 18979232 PMCID: PMC2758385 DOI: 10.1007/s11010-008-9935-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2008] [Accepted: 10/13/2008] [Indexed: 11/16/2022]
Abstract
Arteriogenesis or collateral growth is able to compensate for the stenosis of major arteries. Using differential display RT-PCR on growing and quiescent collateral arteries in a rabbit femoral artery ligation model, we cloned the rabbit full-length cDNA of osteoglycin/mimecan. Osteoglycin was present in the adventitia of collateral arteries as a glycosylated protein without keratan sulfate side chains, mainly produced by smooth muscle cells (SMCs) and perivascular fibroblasts. Northern blot, Western blot, and immunohistochemistry confirmed a collateral artery-specific downregulation of osteoglycin from 6 h to 3 weeks after the onset of arteriogenesis. Treatment of primary SMCs with the arteriogenic protein fibroblast growth factor-2 (FGF-2) resulted in a similar reduction of osteoglycin expression as observed in vivo. Application of the FGF-2 inhibitor polyanethole sulfonic acid (PAS) blocked the downregulation of osteoglycin and interfered with arteriogenesis. From our study we conclude that downregulation of osteoglycin is a fundamental requirement for proper arteriogenesis.
Collapse
|
|
43
|
Katsu M, Koyama H, Maekawa H, Kurihara H, Uchida H, Hamada H. Ex vivo gene delivery of ephrin-B2 induces development of functional collateral vessels in a rabbit model of hind limb ischemia. J Vasc Surg 2008; 49:192-8. [PMID: 18950979 DOI: 10.1016/j.jvs.2008.08.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2008] [Revised: 08/07/2008] [Accepted: 08/07/2008] [Indexed: 11/25/2022]
Abstract
OBJECTIVE In this study, we delivered ephrin-B2 to the ischemic hind limb of rabbits using an ex vivo method of gene transfer and evaluated whether the in vivo application of ephrin-B2 contributed to the development of functional collateral vessels. Ephrin-B2 is a transmembrane ligand of several Eph receptors and bidirectional signaling between ephrin-B2 and Eph-B4 is considered to be essential in angiogenesis and the development of arteries and veins. METHOD The left femoral artery of male Japanese White rabbits was excised to induce limb ischemia, and a primary culture of autofibroblasts was obtained from a skin section. Nineteen days later, the gene expressing ephrin-B2 (ephrin group) or beta-galactosidase gene (control group) was adenovirally transfected to the cultured auto-fibroblasts (5 x 10(6) cells); then 48 hours later, the gene-transduced cells were injected through the left internal iliac artery of the same rabbit. At 28 days after injection, the development of collateral vessels and their function were assessed (control group, n = 12; ephrin group, n = 10). RESULTS The gene expressing ephrin-B2 was successfully transferred to the rabbit autofibroblasts, and ephrin-B2, expressed on the cell membrane, possessed binding ability with its receptor, Eph-B4. Calf blood pressure ratio (control group: 0.523 +/- 0.047 vs ephrin group: 0.658 +/- 0.049, P < .0001), angiographic score (0.344 +/- 0.091 vs 0.525 +/- 0.109, P = .0006), in vivo blood flow of the left internal iliac artery (rest: 11.963 +/- 2.806 vs 17.202 +/- 3.622 mL/min, P = .0014; maximum: 27.652 +/- 10.377 vs 43.400 +/- 7.108 mL/min, P = .0007), collateral conductance (32.740 +/- 7.408 vs 54.489 +/- 18.809 mL/min/100 mm Hg, P = .0097), and capillary density of the left thigh muscle (118.517 +/- 18.669 vs 167.400 +/- 31.271, P = .0002) showed significant improvement in the ephrin-B2 group compared with controls. CONCLUSION These findings suggest that auto-fibroblasts expressing ephrin-B2 potentially promote arteriogenesis as well as angiogenesis in the adult vasculature, resulting in the development of functional collateral vessels to an ischemic lesion.
Collapse
Affiliation(s)
- Masatake Katsu
- Department of Vascular Regeneration, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | | | | | | | | | | |
Collapse
|
|
44
|
Chappell JC, Song J, Burke CW, Klibanov AL, Price RJ. Targeted delivery of nanoparticles bearing fibroblast growth factor-2 by ultrasonic microbubble destruction for therapeutic arteriogenesis. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2008; 4:1769-77. [PMID: 18720443 PMCID: PMC2716217 DOI: 10.1002/smll.200800806] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
Therapeutic strategies in which recombinant growth factors are injected to stimulate arteriogenesis in patients suffering from occlusive vascular disease stand to benefit from improved targeting, less invasiveness, better growth-factor stability, and more sustained growth-factor release. A microbubble contrast-agent-based system facilitates nanoparticle deposition in tissues that are targeted by 1-MHz ultrasound. This system can then be used to deliver poly(D,L-lactic-co-glycolic acid) nanoparticles containing fibroblast growth factor-2 to mouse adductor muscles in a model of hind-limb arterial insufficiency. Two weeks after treatment, significant increases in both the caliber and total number of collateral arterioles are observed, indicating that the delivery of nanoparticles bearing fibroblast growth factor-2 by ultrasonic microbubble destruction may represent an effective and minimally invasive strategy for the targeted stimulation of therapeutic arteriogenesis.
Collapse
Affiliation(s)
- John C. Chappell
- Department of Biomedical Engineering and Robert M. Berne, Cardiovascular Research Center, Box 800759, Health System, Charlottesville VA, 22908 (USA) Fax: (+1) 434-982-3870
| | - Ji Song
- Department of Biomedical Engineering and Robert M. Berne, Cardiovascular Research Center, Box 800759, Health System, Charlottesville VA, 22908 (USA) Fax: (+1) 434-982-3870
| | - Caitlin W. Burke
- Department of Biomedical Engineering and Robert M. Berne, Cardiovascular Research Center, Box 800759, Health System, Charlottesville VA, 22908 (USA) Fax: (+1) 434-982-3870
| | - Alexander L. Klibanov
- University of Virginia, Cardiovascular Medicine and Robert M. Berne, Cardiovascular Research Center, Box 800500, Health System, Charlottesville VA, 22908 (USA) Fax: (+1) 434-982-3183
| | - Richard J. Price
- Department of Biomedical Engineering and Robert M. Berne, Cardiovascular Research Center, Box 800759, Health System, Charlottesville VA, 22908 (USA) Fax: (+1) 434-982-3870
| |
Collapse
|
|
45
|
van Oostrom MC, van Oostrom O, Quax PHA, Verhaar MC, Hoefer IE. Insights into mechanisms behind arteriogenesis: what does the future hold? J Leukoc Biol 2008; 84:1379-91. [DOI: 10.1189/jlb.0508281] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
|
|
46
|
Abstract
PURPOSE OF REVIEW Fibroblast growth factors are potent angiogenic inducers; however, their precise roles in angiogenesis have not been well understood. In this review, we will focus on specific roles played by fibroblast growth factors in neovascularization. RECENT FINDINGS Although fibroblast growth factors promote a strong angiogenic response, it has been suggested that FGF-induced angiogenesis requires activation of the vascular endothelial growth factor system. Recent findings have endorsed the view of indirect contribution of fibroblast growth factor signaling to vascular development. A study using embryoid bodies demonstrated a nonimmediate role played by fibrobalst growth factor receptor 1 in vasculogenesis as vascular endothelial growth factor supplementation was sufficient to promote vascular development in Fgfr1-/- embryoid bodies. Moreover, another line of evidence indicated that myocardial fibroblast growth factor signaling is essential for mouse coronary development. The key role of fibroblast growth factor signaling in this process is Hedgehog activation, which induces vascular endothelial growth factor expression and formation of the coronary vasculature. In addition to vascular endothelial growth factor interaction, fibroblast growth factors can control neovascularization by influencing other growth factors and chemokines such as platelet-derived growth factor, hepatocyte growth factor and monocyte chemoattractant protein-1, contributing to development of mature vessels and collateral arteries. SUMMARY Although fibroblast growth factors are potent angiogenic factors, they may indirectly control neovascularization in concert with other growth factors. Thus, the unique role played by fibroblast growth factors might be organization of various angiogenic pathways and coordination of cell-cell interactions in this process.
Collapse
Affiliation(s)
- Masahiro Murakami
- Angiogenesis Research Center and Section of Cardiology, Department of Medicine, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.
| | | |
Collapse
|
|
47
|
Huang Y, Marui A, Sakaguchi H, Esaki J, Arai Y, Hirose K, Bir SC, Horiuchi H, Maruyama T, Ikeda T, Tabata Y, Komeda M. Sustained Release of Prostaglandin E1 Potentiates the Impaired Therapeutic Angiogenesis by Basic Fibroblast Growth Factor in Diabetic Murine Hindlimb Ischemia. Circ J 2008; 72:1693-9. [DOI: 10.1253/circj.cj-07-0960] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Yuhong Huang
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine
| | - Akira Marui
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine
| | - Hisashi Sakaguchi
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine
| | - Jiro Esaki
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine
| | - Yoshio Arai
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine
| | - Keiichi Hirose
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine
| | - Shyamal Chandra Bir
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine
| | - Hisanori Horiuchi
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
| | | | - Tadashi Ikeda
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine
| | - Yasuhiko Tabata
- Department of Biomaterials, Institute for Frontier Medical Sciences, Kyoto University
| | - Masashi Komeda
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine
| |
Collapse
|
|
48
|
Schirmer SH, van Royen N. Stimulation of collateral artery growth: a potential treatment for peripheral artery disease. Expert Rev Cardiovasc Ther 2007; 2:581-8. [PMID: 15225117 DOI: 10.1586/14779072.2.4.581] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
In the course of peripheral artery occlusive disease, blood flow to peripheral tissue progressively decreases in a substantial portion of patients, leading to insufficient oxygenation and to the occurrence of claudication or critical limb ischemia. Arteriogenesis (collateral artery growth) is a powerful natural mechanism by which large conductance vessels develop that circumvent sites of obstruction. Promising experimental data on both hypoxia-driven angiogenesis as well as monocyte-orchestrated arteriogenesis have raised high hopes for clinical application. Both endothelial growth factors to stimulate angiogenesis (i.e., capillary growth) and monocyte-attracting or -activating substances to stimulate arteriogenesis, have been proposed as potential new therapeutic agents. However, transferring the promising experimental results into clinical practice has been more cumbersome than initially anticipated. Some recent clinical studies are now focusing more specifically on the stimulation of arteriogenesis. This review will critically evaluate the results of preclinical and clinical investigations on the stimulation of vascular growth, focusing specifically on the peripheral circulation.
Collapse
Affiliation(s)
- Stephan H Schirmer
- Department of Internal Medicine III-Cardiology and Angiology, University Hospital Freiburg, Germany.
| | | |
Collapse
|
|
49
|
Abstract
Pharmacological attempts to stimulate the growth of collateral arteries (arteriogenesis) are evolving towards a new treatment option for patients with vascular occlusive diseases. This enlargement of small pre-existing anastomoses towards large conductance arteries takes place independent of local oxygen tension and is driven by changes in luminal shear stress and infiltration of circulating cells. With the increasing knowledge regarding the distinct differences between capillary sprouting (angiogenesis) and arteriogenesis, several cytokines and growth factors have been demonstrated to stimulate the growth of arterial blood vessels in preclinical models of vascular disease. However, the translation towards clinical practice remains difficult and first in-man trials show limited success. Intensive research especially regarding new drug delivery platforms and the potentially serious side effects of pro-arteriogenic therapeutics is warranted before stimulation of arteriogenesis could become a significant treatment option for vascular occlusive diseases. This review focuses on the recent advances in the field of collateral artery growth. In addition, possible means to overcome the hurdles that have hampered the clinical implementation of pro-arteriogenic therapies will be discussed.
Collapse
|
|
50
|
Lipar I, Zalar P, Pohar C, Vlachy V. Thermodynamic characterization of polyanetholesulfonic acid and its alkaline salts. J Phys Chem B 2007; 111:10130-6. [PMID: 17685647 DOI: 10.1021/jp073641q] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Experimental and theoretical results for the thermodynamic properties of polyanetholesulfonic acid and its lithium, sodium, and cesium salts in aqueous solution at 298 K are presented. The osmotic pressure was measured using membrane and vapor pressure apparatus in the concentration range c(m) = 0.001-0.30 monomoles/dm(3). The osmotic coefficients obtained from these measurements were low, from 0.2 to 0.45 in this concentration range, indicating a strong interaction between counterions and polyions. The osmotic coefficients of the polyacid and its lithium and sodium salts appeared to be equal within experimental error, but the results for the cesium salt were lower. This indicates a somewhat stronger binding of cesium ions to the polyanion. In addition, enthalpies of dilution, DeltaH(D), from a certain concentration, m(m), to m(m) = 0.0044 monomoles/kg were measured. The measured heats of dilution were exothermic, with the acid producing the strongest and the cesium salt the weakest effect. These results were compared with previously published data for polyelectrolytes of similar structure, namely, polystyrenesulfonic acid and its alkaline salts. The osmotic pressure results indicate that polystyrenesulfonates bind the counterions more strongly than polyanetholesulfonic acid and its salts. Consistent with this finding, the enthalpies of dilution reveal that more heat is released upon dilution of polyanetholesulfonates (stronger exothermic effect) in comparison with the corresponding solutions of polystyrenesulfonic acid in its alkaline salts. These findings can be explained in terms of the structural differences between the two polyions. The experimental results were analyzed in relation to popular electrostatic theories such as the Manning condensation theory and the Poisson-Boltzmann cell model approach, where the polyion is pictured as a uniformly charged line or cylinder. In addition, we performed Monte Carlo simulations for a model polyanetholesulfonic anion having discrete charges. In all of the calculations, the solvent was treated as a continuum with the dielectric constant of pure water under the conditions of measurement. The theoretical considerations mentioned above yield results in semiquantitative agreement with the measured quantities.
Collapse
Affiliation(s)
- Irena Lipar
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, P.O.B. 537, 1001 Ljubljana, Slovenia
| | | | | | | |
Collapse
|