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Vascular Endothelial Growth Factor receptor binding and downstream signaling pathway. The various pathways that VEGF stimulate within endothelial cells lead to their proliferation, migration, and survival, all of which are necessary for angiogenesis. PI3K, phosphoinositide 3-kinase; Akt/PKB, protein kinase B; p38MAPK, p38 mitogen-activated protein kinase; MEK, mitogen and extracellular kinase; Erk, extracellular regulated kinase. (Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Rini, B et al: Journal of Clinical Oncology 23 (5), 2005: 1028-1043) Vascular Endothelial Growth Factor receptor binding and downstream signaling pathway. The various pathways that VEGF stimulate within endothelial cells lead to their proliferation, migration, and survival, all of which are necessary for angiogenesis. PI3K, phosphoinositide 3-kinase; Akt/PKB, protein kinase B; p38MAPK, p38 mitogen-activated protein kinase; MEK, mitogen and extracellular kinase; Erk, extracellular regulated kinase. (Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Rini, B et al: Journal of Clinical Oncology 23 (5), 2005: 1028-1043)
Source publication
Fractures require adequate stability and blood supply to heal. The vascular supply to long bones is compromised in a fracture, and the ability to heal hinges on the ability of new blood vessels to proliferate from surrounding vessels in a process known as angiogenesis. This process is largely driven by the growth factor, vascular endothelial growth...
Context in source publication
Context 1
... the 165 amino acid peptide being the isoforms with the greatest biological activity [5]. VEGF is produced by endothelial cells, macrophages, fibroblasts, smooth muscle cells, osteo- blasts, and hypertrophic chondrocytes [6][7][8]. Similar to most peptide growth factors, VEGF binds to receptors (VEGFR-1 and 2) on the cell surface of its targets ( Fig. 1) ...
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Method...
Purpose
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Citations
... Researchers discovered the vascular endothelial growth factor (VEGF) receptor on endothelial cells and identified its role in physiological and pathological angiogenesis [23]. VEGF is believed to have the ability to attract stem cells to damaged or diseased bone tissue [24]. However, a study comparing VEGF alone with platelet-rich plasma for the treatment of bone defects in rabbits found that VEGF alone did not produce optimal bone regeneration [25]. ...
... VEGF is recognized as a main growth factor for the stimulation of angiogenesis [42]. Moreover, several studies indicated that VEGF is directly involved in the process of bone regeneration [43,44]. Accordingly, inhibition of VEGF expression has been shown to impair fracture repair and to result in non-union formation [45], whereas stimulation of VEGF expression can accelerate fracture healing [46]. ...
... Accordingly, inhibition of VEGF expression has been shown to impair fracture repair and to result in non-union formation [45], whereas stimulation of VEGF expression can accelerate fracture healing [46]. Notably, the effects of VEGF on fracture repair exceed the sole stimulation of angiogenesis, but also involve the direct stimulation of endochondral and intramembranous fracture healing as well as stem cell recruitment [43,44]. Therefore, it may be speculated that PTH improves bone regeneration in aged mice not only by the stimulation of vascularization but also by directly inducing novel bone formation. ...
Background
Non-union formation still represents a major burden in trauma and orthopedic surgery. Moreover, aged patients are at an increased risk for bone healing failure. Parathyroid hormone (PTH) has been shown to accelerate fracture healing in young adult animals. However, there is no information whether PTH also stimulates bone regeneration in atrophic non-unions in the aged. Therefore, the aim of the present study was to analyze the effect of PTH on bone regeneration in an atrophic non-union model in aged CD-1 mice.
Methods
After creation of a 1.8 mm segmental defect, mice femora were stabilized by pin-clip fixation. The animals were treated daily with either 200 mg/kg body weight PTH 1–34 (n = 17) or saline (control; n = 17) subcutaneously. Bone regeneration was analyzed by means of X-ray, biomechanics, micro-computed tomography (µCT) imaging as well as histological, immunohistochemical and Western blot analyses.
Results
In PTH-treated animals bone formation was markedly improved when compared to controls. This was associated with an increased bending stiffness as well as a higher number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts and CD31-positive microvessels within the callus tissue. Furthermore, PTH-treated aged animals showed a decreased inflammatory response, characterized by a lower number of MPO-positive granulocytes and CD68-positive macrophages within the bone defects when compared to controls. Additional Western blot analyses demonstrated a significantly higher expression of cyclooxygenase (COX)-2 and phosphoinositide 3-kinase (PI3K) in PTH-treated mice.
Conclusion
Taken together, these findings indicate that PTH is an effective pharmacological compound for the treatment of non-union formation in aged animals.
... On the other hand, treatment with VEGF accelerates and improves bone formation [46,47]. Interestingly, recent experimental studies reported that VEGF does not only stimulate angiogenesis during fracture repair, but also directly induces endochondral and intramembranous bone healing as well as stem cell recruitment and osteoblastogenesis [44,48,49]. In the present study, we detected a markedly higher expression of VEGF within the callus tissue of sildenafil-treated animals at 10 weeks after surgery when compared to controls. ...
Non-union formation represents a major complication in trauma and orthopedic surgery. The phosphodiesterase-5 (PDE-5) inhibitor sildenafil has been shown to exert pro-angiogenic and pro-osteogenic effects in vitro and in vivo. Therefore, the aim of the present study was to analyze the impact of sildenafil in an atrophic non-union model in mice. After creation of a 1.8 mm segmental defect, mice femora were stabilized by pin-clip fixation. Bone regeneration was analyzed by means of X-ray, biomechanics, photoacoustic and micro-computed tomography (µCT) imaging as well as histological, immunohistochemical and Western blot analyses at 2, 5 and 10 weeks after surgery. The animals were treated daily with either 5 mg/kg body weight sildenafil (n = 35) or saline (control; n = 35) per os. Bone formation was markedly improved in defects of sildenafil-treated mice when compared to controls. This was associated with a higher bending stiffness as well as an increased number of CD31-positive microvessels and a higher oxygen saturation within the callus tissue. Moreover, the bone defects of sildenafil-treated animals contained more tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts and CD68-positive macrophages and exhibited a higher expression of the pro-angiogenic and pro-osteogenic markers cysteine rich protein (CYR)61 and vascular endothelial growth factor (VEGF) when compared to controls. These findings demonstrate that sildenafil acts as a potent stimulator of angiogenesis and bone regeneration in atrophic non-unions.
... 4 In addition to maintaining homeostasis, angiogenesis plays an important role in fracture repair and regeneration. 5 It is therefore, not surprising that defects in the formation or regeneration of the skeletal vasculature can be a major contributor to numerous pathologies, including tissue necrosis, osteoporosis, and cancer. 6 Understanding the intricate relationship between angiogenesis and osteogenesis may reveal new insights into bone (patho)physiology and open new avenues to treat skeletal disease and regenerate defects. ...
Blood vessel formation is an important initial step for bone formation during development as well as during remodelling and repair in the adult skeleton. This results in a heavily vascularized tissue where endothelial cells and skeletal cells are constantly in crosstalk to facilitate homeostasis, a process that is mediated by numerous environmental signals, including mechanical loading. Breakdown in this communication can lead to disease and/or poor fracture repair. Therefore, this study aimed to determine the role of mature bone cells in regulating angiogenesis, how this is influenced by a dynamic mechanical environment, and understand the mechanism by which this could occur. Herein, we demonstrate that both osteoblasts and osteocytes coordinate endothelial cell proliferation, migration, and blood vessel formation via a mechanically dependent paracrine mechanism. Moreover, we identified that this process is mediated via the secretion of extracellular vesicles (EVs), as isolated EVs from mechanically stimulated bone cells elicited the same response as seen with the full secretome, while the EV-depleted secretome did not elicit any effect. Despite mechanically activated bone cell-derived EVs (MA-EVs) driving a similar response to VEGF treatment, MA-EVs contain minimal quantities of this angiogenic factor. Lastly, a miRNA screen identified mechanoresponsive miRNAs packaged within MA-EVs which are linked with angiogenesis. Taken together, this study has highlighted an important mechanism in osteogenic-angiogenic coupling in bone and has identified the mechanically activated bone cell-derived EVs as a therapeutic to promote angiogenesis and potentially bone repair.
... The osteogenic phase is characterized by angiogenesis, with vascular endothelial growth factor (VEGF) playing a crucial role in regulating angiogenesis and endothelial cell growth. 23 Fischerauer et al. observed that both the hematoma and the subsequent bone trabecule formed after growth plate injury expressed VEGF and VEGF receptor-2, with VEGF expression peaking at the initial osteogenic stage. Bone bridge formation was associated with angiogenesis, which was shown to precede bone bridge formation. ...
... 118 The angiogenesis at the injury site is crucial for both pathways. 23 Anti-VEGF antibody (bevacizumab) was applied to the rat tibial growth plate injury model, and it was found that angiogenesis and bone bridge formation at the injury site decreased after treatment. However, after systemic administration, the length and shortening of the tibia caused by growth plate injury became more evident on day 60, and significant expansion of the hypertrophic zone of the intact growth plate cartilage adjacent to the growth plate injury site was observed. ...
The repair of growth plate injuries is a highly complex process that involves precise spatiotemporal regulation of multiple cell types. While significant progress has been made in understanding the pathological mechanisms underlying growth plate injuries, effectively regulating this process to regenerate the injured growth plate cartilage remains a challenge. Tissue engineering technology has emerged as a promising therapeutic approach for achieving tissue regeneration through the use of functional biological materials, seed cells and biological factors, and it is now widely applied to the regeneration of bone and cartilage. However, due to the unique structure and function of growth plate cartilage, distinct strategies are required for effective regeneration. Thus, this review provides an overview of current research on the application of tissue engineering to promote growth plate regeneration. It aims to elucidates the underlying mechanisms by which tissue engineering promotes growth plate regeneration and to provide novel insights and therapeutic strategies for future research on the regeneration of growth plate.
... The mechanisms of neovascularization, which is responsible for the formation of new blood vessels, and angiogenesis, are two important components of regenerative processes, including bone regeneration [45] It is argued that EPO influences both mechanisms and, therefore, may affect bone regeneration [46] In previous studies, EPO has been shown to increase the number of stem cells and progenitor cells in bone marrow and EPO causes the release of endothelial progenitor cells (EPCs), which have been shown to contribute to the bone-healing process [47]. Garcia et al. reported that the number of EPCs in peripheral blood was significantly increased in animals treated with EPO [19]. ...
In this experimental study, the prophylactic effect of systemically administered erythropoietin (EPO) in medication-related osteonecrosis of the jaw (MRONJ) was evaluated. The osteonecrosis model was established using 36 Sprague Dawley rats. EPO was systemically applied before and/or after tooth extraction. Groups were formed based on the application time. All samples were evaluated histologically, histomorphometrically, and immunohistochemically. A statistically significant difference in new bone formation was observed between the groups (p < 0.001). When new bone-formation rates were compared, no significant differences were observed between the control group and the EPO, ZA+PostEPO, and ZA+Pre-PostEPO groups (p = 1, 0.402, and 1, respectively); however, this rate was significantly lower in the ZA+PreEPO group (p = 0.021). No significant differences in new bone formation were observed between the ZA+PostEPO and ZA+PreEPO groups (p = 1); however, this rate was significantly higher in the ZA+Pre-PostEPO group (p = 0.009). The ZA+Pre-PostEPO group demonstrated significantly higher intensity level in VEGF protein expression than the other groups (p < 0.001). Administering EPO two weeks pre-extraction and continuing EPO treatment for three weeks post-extraction in ZA-treated rats optimized the inflammatory reaction, increased angiogenesis by inducing VEGF, and positively affected bone healing. Further studies are needed to determine the exact durations and doses.
... Studies have highlighted the angiogenic effect of PDRN [31,32]. Angiogenesis has an important role in fracture healing and repair [33] and, consequently, has cell signaling pathways that are coupled with osteogenesis. Wound healing and tube formation analysis was performed to examine the pro-angiogenic ability of the PME2/PN using human umbilical vein endothelial cells (HUVECs) cultured in conditioned medium immersed the composites for 24 h (Fig. 3A and B). ...
... Angiogenesis-related gene expression was evaluated using qRT-PCR (Fig. 3C). VEGF-A, a major regulator of angiogenesis, is secreted by osteoblasts and hypertrophic chondrocytes and can be involved in osteoblast differentiation [33]. Ang1 is expressed in endothelial cells and has important roles in vascular growth, remodeling, and maturation. ...
Despite current developments in bone substitute technology for spinal fusion, there is a lack of adequate materials for bone regeneration in clinical applications. Recombinant human bone morphogenetic protein-2 (rhBMP-2) is commercially available, but a severe inflammatory response is a known side effect. Bone graft substitutes that enhance osteogenesis without adverse effects are needed. We developed a bioactive molecule-laden PLGA composite with multi-modulation for bone fusion. This bioresorbable composite scaffold was considered for bone tissue engineering. Among the main components, magnesium hydroxide (MH) aids in reduction of acute inflammation affecting disruption of new bone formation. Decellularized bone extracellular matrix (bECM) and demineralized bone matrix (DBM) composites were used for osteoconductive and osteoinductive activities. A bioactive molecule, polydeoxyribonucleotide (PDRN, PN), derived from trout was used for angiogenesis during bone regeneration. A nano-emulsion method that included Span 80 was used to fabricate bioactive PLGA-MH-bECM/DBM-PDRN (PME2/PN) composite to obtain a highly effective and safe scaffold. The synergistic effect provided by PME2/PN improved not only osteogenic and angiogenic gene expression for bone fusion but also improved immunosuppression and polarization of macrophages that were important for bone tissue repair, using a rat model of posterolateral spinal fusion (PLF). It thus had sufficient biocompatibility and bioactivity for spinal fusion.
... 35,62,63 It has been suggested that BFR exercise results in increased mobilization of hematopoietic stem progenitor cells, proliferation of myogenic stem cells, increased cytokine responses, increases in the number of circulating CD34+/KDR+ endothelial progenitor cells, and increased VEGF. 32,33,35,[54][55][56] Thus, in this case report, BFR was used during exercise to "amplify" the yield / healing capacity of PRP by utilization pre-exsanguination and during rehabilitation, respectively. A recent study suggested that BFR can be considered a way to manipulate point-of-care blood products such as PRP to increase product yield. ...
Background
Platelet-rich plasma (PRP) and prolotherapy have resulted in promising outcomes in patients with various types of shoulder injuries. However, there is a lack of preliminary evidence supporting preparation of PRP production, timely application of these therapies and regenerative rehabilitation protocols. The purpose of this case report is to describe the distinct method including orthobiologic preparation, tissue-specific treatment and regenerative rehabilitation of an athlete with a complex shoulder injury.
Case Presentation
A 15y/o competitive female wrestler with a complex shoulder injury presented to the clinic after unsuccessful conservative rehabilitation. Unique methods were incorporated to optimize PRP production, specific tissue healing and regenerative rehabilitation. Multiple injuries required different orthobiologic interventions at different time frames, in order to promote optimal healing and stability of the shoulder.
Outcomes
The described interventions resulted in successful outcomes including pain, disability, full return to sport, and regenerative tissue healing confirmed with diagnostic imaging.
Level of Evidence
5
... This study suggests that the hematoma, which is a fibrin matrix deposition that occurred within hours to days post fracture, acts as a VEGF reservoir. 67,68 In this inflammatory phase, VEGF is concentrated in the hematoma in response to hypoxic conditions that occur. VEGF at this stage plays a role in the formation of granulation tissue, works by triggering chemotaxis of neutrophils and other inflammatory cells and increasing vascular permeability. ...
... VEGF plays an autocrine and paracrine role in invading the vascular into the callus, which stops and changes the program originally intended for callus formation to become a bone formation program. 67 This is confirmed by the study of Yuasa et al where the process of revascularization at the fracture site was found to be inversely proportional to the size of the soft callus and the size of the hard callus. 50 There is data heterogeneity of the included studies which is not measured quantitatively in this study, such as various animals used, fracture methods, micro-CT angiography methods, and methods of RT-PCR analysis. ...
Angiogenesis plays an important role in fracture healing with vascular endothelial growth factor (VEGF) as the main protein involved. Micro-computed tomography (CT) angiography may be used to analyze this revascularization with several parameters such as number of branches, total volume, and diameter. This systematic review is aimed to assess available studies on the temporal pattern of vascular imaging on micro-CT angiographs, especially in terms of the number of branches, total volume, and diameter as well as the temporal pattern of VEGF mRNA expression as the molecular comparison during bone fracture healing. This review was conducted according to the PRISMA guidelines. Electronic database searches were performed using PubMed, ProQuest, ScienceDirect, EBSCOhost, Taylor & Francis Online, and hand searching. The search strategy and keywords were adjusted to each database using the Boolean operators and other available limit functions to identify most relevant articles based on our inclusion and exclusion criteria. Screening and filtration were done in several stages by removing the duplicates and analyzing each title, abstract, and full-text in all included entries. Data extraction was done for syntheses to summarize the temporal pattern of each parameter. A total of 28 articles were eligible and met all criteria, 11 articles were synthesized in its angiograph's analysis, 16 articles were synthesized in its VEGF mRNA expression analysis, and 1 article had both parameters analyzed. The overall temporal pattern of both three micro-CT angiographic parameters and VEGF mRNA expression was in line qualitatively. The number of branches, total volume, and diameter of the blood vessels in micro-CT angiography showed an exponential rise at week 2 and decline at week 3 of fracture healing, with the VEGF mRNA expression concurrently showing a consistent pattern in the phase.
... In bone fractures, the architecture of bone and blood vessels is disrupted at the site of injury. Consequently, the formation of fracture hematoma occurs, which contains immune and bone marrow cells, and this process is called the inflammation phase, an initiation of fracture healing [1,2]. ...
Angiogenesis plays an important role in the development of bone and bone regeneration to provide the required molecules. Mesenchymal stem cells (MSCs) are pluripotent, self-renewing, and spindle-shaped cells, which can differentiate into multiple lineages such as chondrocytes, osteocytes, and adipocytes. MSCs derived from bone marrow (BMMSCs), adipose tissue (ADMSCs), and Wharton’s jelly (UCMSCs) are popular in the field of tissue regeneration. MSCs have been proposed that can promote bone regeneration by enhancing vascularization. In this study, the angiogenic potential of secretomes of undifferentiated and osteo-differentiated BMMSCs, ADMSCs, and UCMSCs seeded on human decellularized allogeneic bone were compared. Human umbilical vein endothelial cells (HUVECs) were treated with MSC secretomes. Cell growth, cell migration, and angiogenesis of HUVECs were analyzed by MTT, wound healing, and tube formation assays. Angiogenic gene expression levels of MSCs were evaluated using real-time quantitative PCR. Antibody neutralization was performed to validate the candidate target. Our study demonstrates that the angiogenic gene expression profile is tissue-dependent and the angiogenic ability of secretomes is independent of the state of differentiation. We also explore that IL-1b is important for MSC angiogenic potential. Taken together, this study proves that IL-1b in the secretomes plays a vital role in angiogenesis.
