Vascular Endothelial Growth Factor In Group Research Articles

Angiogenic lipid-based drug delivery system (PhytoSolve) for treatment of a thin endometrium in animal model

Impaired vascular growth resulting from reduced vascular endothelial growth factor (VEGF) in the epithelial tissue of the glands is a primary cause of thin endometrium. Inducing angiogenesis offers a possible therapeutic strategy for this condition. This study aimed to develop a novel drug delivery system using S75 lipoid loaded with VEGF for thin endometrium therapy. The formulation of PhytoSolve consisted of a combination of lipid S75, glycerol, and MCT oil, which was prepared utilizing a probe sonicator. Female NMRI mice (n=30) were divided into six groups: control, sham, thin endometrial model, VEGF treatment, PhytoSolve treatment, and VEGF/PhytoSolve treatment. A thin endometrial model was induced by injecting 95 % ethanol. After the treatment period, tissue samples were collected to assess the endometrial thickness—the mean particle size of the PhytoSolve formulation measured 67.57±7.07 nm. Approximately 40 % of the loaded VEGF was released within the first 24 hours, followed by a sustained release rate of 10–20 % daily. The PhytoSolve group containing VEGF exhibited significantly increased endometrial thickness compared to the VEGF group (P<0.05). S75 lipoid-based PhytoSolve loaded with VEGF effectively promoted blood vessel formation. The combination of PhytoSolve S75 and VEGF holds promise for developing a biocompatible drug delivery system with therapeutic potential for treating thin endometrium and various other biomedical applications.

The effects of SDF-1 combined application with VEGF on femoral distraction osteogenesis in rats.

Bone regeneration and mineralization can be achieved by means of distraction osteogenesis (DO). In the present study, we investigated the effect of stromal cell-derived factor 1 (SDF-1) and vascular endothelial growth factor (VEGF) on the new bone formation during DO in rats. Forty-eight Sprague-Dawley rats were randomized into four groups of 12 rats each. We established the left femoral DO model in rats and performed a mid-femoral osteotomy, which was fixed with an external fixator. DO was performed at 0.25 mm/12 h after an incubation period of 5 days. Distraction was continued for 10 days, resulting in a total of 5 mm of lengthening. After distraction, the solution was locally injected into the osteotomy site, once a day 1 ml for 1 week. One group received the solvent alone and served as the control, and the other three groups were treated with SDF-1, VEGF, and SDF-1with VEGF in an aqueous. Sequential X-ray radiographs were taken two weekly. The regeneration was monitored with the use of micro-CT analysis, mechanical testing, and histology. Radiographs showed accelerated regenerate ossification in the SDF-1, VEGF, and SDF-1 with the VEGF group, with a larger amount of new bone compared with the control group, especially SDF-1 with the VEGF group. Micro-CT analysis and biomechanical tests showed Continuous injection of the SDF-1, VEGF, and SDF-1 with VEGF during the consolidation period significantly increased bone mineral density bone volume, mechanical maximum loading, and bone mineralization of the regenerate. Similarly, the expression of osteogenic-specific genes, as determined by real-time polymerase chain reaction , was significantly higher in SDF-1 with the VEGF group than in the other groups. Histological examination revealed more new trabeculae in the distraction gap and more mature bone tissue for the SDF-1 with the VEGF group. SDF-1 and VEGF promote bone regeneration and mineralization during DO, and there is a synergistic effect between the SDF-1 and VEGF. It is possible to provide a new and feasible method to shorten the period of treatment of DO.

Radiogenomic Analysis of Vascular Endothelial Growth Factor in Patients With Glioblastoma.

This article aims to predict the presence of vascular endothelial growth factor (VEGF) expression and to predict the expression level of VEGF by machine learning based on preoperative magnetic resonance imaging (MRI) of glioblastoma (GBM). We analyzed the axial T2-weighted images (T2WI) and T1-weighted contrast-enhancement images of preoperative MRI in 217 patients with pathologically diagnosed GBM. Patients were divided into negative and positive VEGF groups, with the latter group further subdivided into low and high expression. The machine learning models were established with the maximum relevance and minimum redundancy algorithm and the extreme gradient boosting classifier. The area under the receiver operating curve (AUC) and accuracy were calculated for the training and validation sets. Positive VEGF in GBM was 63.1% (137/217), with a high expression ratio of 53.3% (73/137). To predict the positive and negative VEGF expression, 7 radiomic features were selected, with 3 features from T1CE and 4 from T2WI. The accuracy and AUC were 0.83 and 0.81, respectively, in the training set and were 0.73 and 0.74, respectively, in the validation set. To predict high and low levels, 7 radiomic features were selected, with 2 from T1CE, 1 from T2WI, and 4 from the data combinations of T1CE and T2WI. The accuracy and AUC were 0.88 and 0.88, respectively, in the training set and were 0.72 and 0.72, respectively, in the validation set. The VEGF expression status in GBM can be predicted using a machine learning model. Radiomic features resulting from data combinations of different MRI sequences could be helpful.

Effects of Vascular Endothelial Growth Factor on YAP/TAZ Signaling in Trabecular Meshwork Cells

Purpose: To investigate the effects of vascular endothelial growth factor (VEGF) on yes-associated protein (YAP)/transcriptional coactivator with a PDZ-binding motif (TAZ), a Hippo pathway-related transcription factor, and the role of YAP/TAZ induced by trabecular meshwork stimulation.Methods: Human trabecular meshwork cells were cultured and treated with various VEGF concentrations to verify cell cytotoxicity using the CCK-8 solution. Transforming growth factor β-2 (TGFβ2; 5 ng/mL) and VEGF (30 ng/mL) were applied and YAP/TAZ expression was assessed by western blotting, reverse transcription quantitative polymerase chain reaction and immunocytochemistry. Fibronectin, collagen 1, and myocilin expression were also assessed by western blotting. The cells were stained using Alexa Fluor 488-phalloidin to observe F-actin changes.Results: YAP and TAZ expression increased following TGFβ2 and VEGF treatment for 24 hours. Fibronectin and collagen 1 increased significantly in all three treatment groups, while myocilin increased in the TGFβ2 and TGFβ2+VEGF groups. The F-actin staining showed increased cross-linking in the trabecular meshwork cells.Conclusions: VEGF induced YAP/TAZ signaling and increased trabecular meshwork cell fibrosis. Based on the functional changes caused by VEGF, it is suggested that VEGF and YAP/TAZ may increase aqueous humor outflow resistance in trabecular meshwork cells.

Suppressive role of vascular endothelial growth factor on intestinal apoptosis in induced necrotizing enterocolitis in rats.

Necrotizing enterocolitis (NEC) is a devastating disease that can cause mortality in preterm babies. NEC may develop through an apoptotic pathway that is known to be inhibited by vascular endothelial growth factor (VEGF). This study determined whether VEGF exerted a protective effect against the development of NEC and apoptosis in rats. To determine the effect of VEGF in NEC rats, neonatal rats were randomized into 4 groups: the control group, the NEC group, the NEC + intraperitoneal VEGF (50 ng/kg) group (NEC + VEGF IP group), and the NEC + oral VEGF (50 ng/kg) group (NEC + VEGF OR group). NEC was induced by lipopolysaccharide/hypoxia and cold stress. The animals were sacrificed 72 hours later. After laparotomy, we obtained a region of the proximal small bowel from the ileocecal valve about 18 cm in length. The NEC histological grade, apoptosis histological score, and caspase-3 activity were lower in the NEC + VEGF IP and OR groups than in the NEC group. In the NEC + VEGF IP and OR groups, the messenger RNA expression of apoptotic and inflammatory genes, such as Bax, NF-κB, p53, Fas, FasL, and PAF-R, but not that of Bcl-2, was decreased, as was the Bax/Bcl-2 protein ratio. Histological analysis revealed that the apoptosis-blocking effect of VEGF was more effective in the NEC + VEGF IP group than in the NEC + VEGF OR group. We identified apoptotic and inflammatory genes to confirm the preventive effect of VEGF pretreatment on NEC in rats. This study presents a novel approach to prevent apoptosis via VEGF pretreatment in rats with lipopolysaccharide/hypoxia-induced NEC.

Photo-crosslinked GelMA loaded with dental pulp stem cells and VEGF to repair critical-sized soft tissue defects in rats

BackgroundTissue engineering of skin and mucosa is essential for the esthetic and functional reconstruction of individuals disfigured by trauma, resection surgery, or severe burns while overcoming the limited amount of autograft and donor site morbidity. PurposeWe aimed to determine whether a combination of Gelatin-methacryloyl (GelMA) hydrogel scaffold alone or loaded with either dental pulp stem cells (DPSCs) and/or vascular endothelial growth factor (VEGF) could improve skin wound healing in rats. Materials and MethodsFour 10 mm full-thickness skin defects were created on the dorsum of 15 Sprague-Dawley rats. The wounds were treated with GelMA alone, GelMA+DPSCs, or GelMA+DPSCs+VEGF. Unprotected wounds were used as controls. Animals were euthanized at 1-, 2-, and 4 weeks post-surgery, and the healing wounds were harvested for clinical, histological, and RT-PCR analysis. ResultsNo signs of clinical inflammation were observed among all groups. Few and sparse mononuclear inflammatory cells were observed in GelMA+DPSCs and GelMA+DPSCs+VEGF groups at 2 weeks, with complete epithelialization of the wounds. At 4 weeks, the epidermis in GelMA+DPSCs and GelMA+DPSCs+VEGF groups was indistinguishable from the empty defect and GelMA groups. The decrease in cellularity and increase in density of collagen fibers were observed over time in both GelMA+DPSCs and GelMA+DPSCs+VEGF groups but were more evident in the GelMA+DPSCs+VEGF group. The GelMA+DPSCs+VEGF group showed a higher expression of the KER 10 gene at all time points compared with the other groups. Expression of Col1 A1 and TGFβ-1 were not statistically different over time neither among the groups. ConclusionGelMA scaffolds loaded with DPSCs, and VEGF accelerated the re-epithelialization of skin wounds.

Vascular endothelial growth factor attenuates neointimal hyperplasia of decellularized small-diameter vascular grafts by modulating the local inflammatory response.

Small-diameter vascular grafts (diameter <6mm) are in high demand in clinical practice. Neointimal hyperplasia, a common complication after implantation of small-diameter vascular grafts, is one of the common causes of graft failure. Modulation of local inflammatory responses is a promising strategy to attenuates neointimal hyperplasia. Vascular endothelial growth factor (VEGF) is an angiogenesis stimulator that also induces macrophage polarization and modulates inflammatory responses. In the present study, we evaluated the effect of VEGF on the neointima hyperplasia and local inflammatory responses of decellularized vascular grafts. In the presence of rhVEGF-165 in RAW264.6 macrophage culture, rhVEGF-165 induces RAW264.6 macrophage polarization to M2 phenotype. Decellularized bovine internal mammary arteries were implanted into the subcutaneous and infrarenal abdominal aorta of New Zealand rabbits, with rhVEGF-165 applied locally to the adventitial of the grafts. The vascular grafts were removed en-bloc and submitted to histological and immunofluorescence analyses on days 7 and 28 following implantation. The thickness of the fibrous capsule and neointima was thinner in the VEGF group than that in the control group. In the immunofluorescence analysis, the number of M2 macrophages and the ratio of M2/M1 macrophages in vascular grafts in the VEGF group were higher than those in the control group, and the proinflammatory factor IL-1 was expressed less than in the control group, but the anti-inflammatory factor IL-10 was expressed more. In conclusion, local VEGF administration attenuates neointimal hyperplasia in decellularized small-diameter vascular grafts by inducing macrophage M2 polarization and modulating the inflammatory response.

Administration of botulinum toxin a and vascular endhotelial growth factor reduce norepinephrine levels and increase viability of modified mcfarlane flap in wistar rat

Local hyperadrenergic states after a random flap elevation mediated by humoral vasoconstrictors can lead to flap necrosis. This study aimed to evaluate the effect of Botulinum Toxin A (BoNT-A) on reducing levels of Norepinephrine (NE) as the main humoral vasoactive substance, as well as its additive effect with Vascular Endothelial Growth Factor (VEGF) in increasing the viability of random flap. 28 Wistar Rats with Caudally Based Modified McFarlane Flap were divided into four groups. Group I received BoNT-A 3 days before flap elevation, group II received VEGF immediately after flap elevation, group III received a combination of BoNT-A and VEGF, group IV was a control group. Result in this study NE levels lowest was found in the BoNT-A+VEGF combination group (94.63 ± 5 .25 ng/ml, p&lt;0.05 in group I, p&lt;0.01 in groups II and IV). The highest value of FVR was shown in the BoNT-A+VEGF combination group (93.37 ± 2.19 %, p &lt; 0.05 in group I, p &lt; 0.01 in groups II and IV). Meanwhile, the increase in flap viability in the VEGF group was not statistically significant. So Conclusion administration of BoNT-A in combination with VEGF can increase the viability of random flaps by decreasing NE levels.

Outcomes of patients with advanced non-clear cell renal cell carcinoma treated with first-line immune checkpoint inhibitor therapy

BackgroundImmune checkpoint inhibitors (ICI) have demonstrated impressive activity in metastatic clear-cell renal cell carcinoma (ccRCC) and have become standard treatment options for patients with advanced disease. Data supporting the effectiveness of ICI-based therapy in advanced non-clear cell RCC (nccRCC) is more limited. MethodsWe performed a retrospective analysis using the International Metastatic RCC Database Consortium (IMDC) to evaluate the outcomes of patients with advanced nccRCC. Patients were classified into three groups based on first-line therapy: ICI-based therapy (monotherapy or combination), vascular endothelial growth factor (VEGF) inhibitor monotherapy, or mammalian target of rapamycin (mTOR) inhibitor monotherapy. The primary outcome was overall survival (OS). Secondary outcomes were time to treatment failure (TTF) and objective response rate (ORR). We used the Kaplan–Meier method to compare OS and TTF between treatment groups and Cox proportional hazards models to adjust for prognostic covariates. ResultsWe identified a total of 1145 patients with metastatic nccRCC. The most common subtype was papillary RCC (54.9%). For first-line therapy, 74.3% received VEGF monotherapy, 15% received mTOR monotherapy, and 10.7% received ICI-based therapy. Median OS in the ICI group was 28.6 months, versus 16.4 months in the VEGF group and 12.2 months in the mTOR group. Median TTF in the ICI group was 6.9 months, versus 5.0 months in the VEGF group and 3.9 months in the mTOR group. ORR was 27.2% in the ICI group, 14.5% in the VEGF group, and 9% in the mTOR group. After adjusting for the IMDC risk group, histological subtype, and age, the hazard ratio for OS was 0.57 (95% CI 0.42–0.78, p < 0.0001) for ICI versus VEGF and 0.50 (95% CI 0.36–0.71, p < 0.0001) for ICI versus mTOR. ConclusionsIn advanced nccRCC, first-line ICI-based treatment appears to be associated with improved OS compared to VEGF and mTOR targeted therapy. These results should be confirmed in prospective randomised trials.

Application of vascular endothelial growth factor at different phases of intestinal ischemia/reperfusion: What are its effects on oxidative stress, inflammation and telomerase activity?

Intestinal ischemic reperfusion injury (IRI) represents a great challenge in clinical practice, with high morbidity and mortality. Vascular endothelial growth factor (VEGF), as a signal protein, contributes to vasculogenesis and angiogenesis. To evaluate the local effectiveness of VEGF following intestinal IRI and its relation with application time. Thirty Wistar albino rats were allocated to 5 groups and underwent laparotomy. The superior mesenteric arteries (SMA) were dissected in 4 groups, while the control group (Gr C) underwent a resection of small and large intestines. The VEGF group (Gr V) received VEGF following SMA dissection, with no further intervention, and the remaining 3 groups were subjected to ischemia for 90 min through occlusion of SMA and reperfusion for 4 h. Ischemic reperfusion group (Gr I/R) received no additional medication, while the remaining 2 groups received VEGF just before ischemia (Gr V+I/R) and during reperfusion (Gr I/R+V). Both applications of VEGF caused decreases in plasma levels of interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), intestinal malondialdehyde (MDA), oxidized glutathione, protein carbonyl levels, and increases in intestinal total glutathione and superoxide dismutase (SOD) levels. Telomerase activity, which disappeared for Gr I/R, was found to be elevated following both treatment groups. Similarly, the histopathological scores were found better for both treatment groups, but Gr V-I/R represented best outcomes. The findings of our study revealed that VEGF, applied either before ischemia or during reperfusion, is effective on local damage following intestinal IRI. By interpreting the biochemical analysis and histopathological findings, we conclude either treatment option to be considered according to the reason of intestinal IRI.

Experimental abdominal aortic aneurysm growth is inhibited by blocking the JAK2/STAT3 pathway

BackgroundThe JAK/STAT pathway is a vital transcription signaling pathway that regulates gene expression and cellular activity. Our recently published study highlighted the role of IL-17A in abdominal aortic aneurysm (AAA) formation and rupture. IL-17A has been proven to upregulate vascular endothelial growth factor (VEGF) expression in some diseases. However, no study has demonstrated the relationships among JAK2/STAT3, IL-17A and VEGF. Therefore, we hypothesized that IL-17A may up-regulate VEGF expression via the JAK2/STAT3 signaling pathway to amplify the inflammatory response, exacerbate neovascularization, and accelerate AAA progression. MethodsTo fully verify our hypothesis, two separate studies were performed: i) a study investigating the influence of JAK2/STAT3 on AAA formation and progression. ii) a study evaluating the relationship among IL-17A, JAK2/STAT3 and VEGF. Human tissues were collected from 7 AAA patients who underwent open surgery and 7 liver transplantation donors. All human aortic tissues were examined by histological and immunohistochemical staining, and Western blotting. Furthermore, mouse aortic tissues were also examined by histological and immunohistochemical staining and Western blotting, and the mouse aortic diameters were assessed by high-resolution Vevo 2100 microimaging system. ResultsAmong human aortic tissues, JAK2/STAT3, IL-17A and VEGF expression levels were higher in AAA tissues than in control tissues. Group treated with WP1066 (a selective JAK2/STAT3 pathway inhibitor), IL-17A, and VEGF groups had AAA incidences of 25%, 40%, and 65%, respectively, while the control group had an incidence of 75%. Histopathological analysis revealed that the IL-17A- and VEGF-related inflammatory responses were attenuated by WP1066. Thus, blocking the JAK2/STAT3 pathway with WP1066 attenuated experimental AAA progression. In addition, in study ii, we found that IL-17A siRNA seemed to attenuate the expression of IL-17A and VEGF in vivo study; treatment with VEGF siRNA decreased the expression of VEGF, while IL-17A expression remained high. In an in vitro study, rhIL-17A treatment increased JAK2/STAT3 and VEGF expression in macrophages in a dose-dependent manner. ConclusionBlocking the JAK2/STAT3 pathway with WP1066 (a JAK2/STAT3 specific inhibitor) attenuates experimental AAA progression. During AAA progression, IL-17A may influence the expression of VEGF via the JAK2/STAT3 signaling pathway. This potential mechanism may suggest a novel strategy for nonsurgical AAA treatment.

Effects and mechanism of rat epidermal stem cells treated with exogenous vascular endothelial growth factor on healing of deep partial-thickness burn wounds in rats

Effects and mechanism of rat epidermal stem cells treated with exogenous vascular endothelial growth factor on healing of deep partial-thickness burn wounds in rats

Injectable hydrogel delivering bone morphogenetic protein-2, vascular endothelial growth factor, and adipose-derived stem cells for vascularized bone tissue engineering

We aimed to evaluate the integration of stem cells with injectable microspheres loaded with growth factors using a chitosan (CS) scaffold to promote healthy bone regeneration. We prepared and injected CS scaffolds containing adipose-derived stem cell (ADSC)-, vascular endothelial growth factor (VEGF)-, and bone morphogenetic protein-2 (BMP-2)-loaded nanohydroxyapatite (nHA)/poly lactic-co-glycolic acid microspheres (PLGAs) into critical-sized mandibular bone defects in rabbits. This injectable hydrogel displayed excellent physicochemical properties and degradability and achieved sustainable release and bioactivity preservation for both BMP-2 and VEGF. Computed tomography imaging and gross and histological observations indicated that bone defect cavities in the control group did not narrow and were filled with granulation tissue. Limited new bone formation for the first 12 weeks post-operation was observed in the defect cavities of the VEGF group; the scaffold degraded gradually and was replaced with fibrous connective tissue. In the BMP-2 or BMP-2/VEGF groups, bone defect cavities narrowed with time and healed completely after 12 weeks; scaffolds gradually degraded and infiltrated tightly into the surrounding tissues. Overall, the BMP-2/VEGF group demonstrated greater new bone formation, faster healing, and better callus remodeling. Simultaneous application of VEGF and BMP-2, therefore, promoted ossification and vascularization in critical-sized rabbit mandibular bone defects.

Effects of vascular endothelial growth factor supplementation and alginate embedding on human oocyte maturation in vitro

Objective: To evaluate whether the use of vascular endothelial growth factor (VEGF) with alginate increases oocyte maturation following in vitro maturation.Methods: This experimental study was performed on 150 immature oocytes (germinal vesicle oocytes) from females who were candidates for assisted reproductive technology. The germinal vesicle oocytes were randomly placed in the control, alginate, and VEGF plus alginate groups. The basic culture medium for oocytes culture (tissue culture medium 199, follicle-stimulating hormone 0.075 IU/mL, and fetal bovine serum 10%) was used in the control, alginate, and VEGF plus alginate groups. For the treatment groups (alginate, and VEGF plus alginate groups), alginate (8%) and VEGF (5 ng/mL) were added to the basic culture medium. After culture, immature oocytes were considered as oocytes unchanged in the nucleus whereas oocytes with a polar body were considered as mature oocytes (metaphase II stage). The mature oocytes in each group were fertilized by intracytoplasmic sperm injection and formed embryos were evaluated by reverse microscope.Results: The oocyte maturation rate (metaphase II) significantly (P < 0.05) increased in the alginate plus VEGF group as compared with the alginate alone and control groups during in vitro maturation. On day 2, the cleavage rates were significantly different in the matured oocytes between the treatment groups and the control group. The percentage of the two-cell stage, four-cell stage and eight-cell embryos was significantly higher in the treatment groups compared with the control group (P <0.05).Conclusions: Supplementation of VEGF with alginate can improve oocyte maturation in culture media. VEGF with alginate may promote the quality of nuclear and cytoplasmic maturation of human oocytes in vitro.

Role of Vascular Endothelial Growth Factor and Human Umbilical Vein Endothelial Cells in Designing An In Vitro Vascular-Muscle Cellular Model Using Adipose-Derived Stem Cells.

Objective Researchers have been interested in the creation of a favorable cellular model for use in vascular-muscle tissue engineering. The main objective of this study is to determine the myogenic effects of vascular endothelial growth factor (VEGF) and human umbilical vein endothelial cells (HUVECs) on adipose-derived stem cells (ADSCs) to achieve an in vitro vascular-muscle cellular model. Materials and Methods The present experimental research was conducted on two primary groups, namely ADSCs monoculture and ADSCs/HUVECs co-culture that were divided into control, horse serum (HS), and HS/VEGF differentiation subgroups. HUVECs were co-cultured by ADSC in a ratio of 1:1. The myogenic differentiation was evaluated using the reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence in different experimental groups. The interaction between ADSCs and HUVECs, as well as the role of ADSCs conditional medium, was investigated for endothelial tube formation assay. Results Immunofluorescence staining indicated that Tropomyosin was positive in ADSCs and ADSCs and HUVECs co-culture groups on HS and HS/VEGF culture medium. Furthermore, the MyHC2 gene expression significantly increased in HS and HS/VEGF groups in comparison with the control group (P<0.001). More importantly, there was a significant difference in the mRNA expression of this gene between ADSCs and ADSCs and HUVECs co-culture groups on HS/VEGF culture medium (P<0.05). Current data revealed that the co-culture of ADSCs and HUVECs could develop endothelial network formation in the VEGF-loaded group. Also, the ADSCs-conditioned medium improved the viability and formation of the endothelial tube in the HS and VEGF groups, respectively. ConclusionIt was concluded that ADSCs/HUVECs co-culture and dual effects of VEGF can lead to the formation of differentiated myoblasts in proximity to endothelial network formations. These in vitro cellular models could be potentially used in vascular-muscle tissue engineering implanted into organ defects where muscle tissue and vascular regeneration were required.

The combinatory effect of sinusoidal electromagnetic field and VEGF promotes osteogenesis and angiogenesis of mesenchymal stem cell-laden PCL/HA implants in a rat subcritical cranial defect

BackgroundRestoration of massive bone defects remains a huge challenge for orthopedic surgeons. Insufficient vascularization and slow bone regeneration limited the application of tissue engineering in bone defect. The effect of electromagnetic field (EMF) on bone defect has been reported for many years. However, sinusoidal EMF (SEMF) combined with tissue engineering in bone regeneration remains poorly investigated.MethodsIn the present study, we investigated the effect of SEMF and vascular endothelial growth factor (VEGF) on osteogenic and vasculogenic differentiation of rat bone marrow-derived mesenchymal stem cells (rBMSCs). Furthermore, pretreated rBMSC- laden polycaprolactone-hydroxyapatite (PCL/HA) scaffold was constructed and implanted into the subcritical cranial defect of rats. The bone formation and vascularization were evaluated 4 and 12 weeks after implantation.ResultsIt was shown that SEMF and VEGF could enhance the protein and mRNA expression levels of osteoblast- and endothelial cell-related markers, respectively. The combinatory effect of SEMF and VEGF slightly promoted the angiogenic differentiation of rBMSCs. The proteins of Wnt1, low-density lipoprotein receptor-related protein 6 (LRP-6), and β-catenin increased in all inducted groups, especially in SEMF + VEGF group. The results indicated that Wnt/β-catenin pathway might participate in the osteogenic and angiogenic differentiation of rBMSCs. Histological evaluation and reconstructed 3D graphs revealed that tissue-engineered constructs significantly promoted the new bone formation and angiogenesis compared to other groups.ConclusionThe combinatory effect of SEMF and VEGF raised an efficient approach to enhance the osteogenesis and vascularization of tissue-engineered constructs, which provided a useful guide for regeneration of bone defects.

Efficacy and safety of bevacizumab combined with chemotherapy in symptomatic brain metastases from lung adenocarcinoma: a retrospective analysis.

Currently, the treatment of symptomatic brain metastases from lung adenocarcinoma has remained difficult. Bevacizumab combined with chemotherapy is one of the standard treatments of lung adenocarcinoma. This study was designed to investigate the efficacy and safety of bevacizumab combined with chemotherapy in symptomatic brain metastases from lung adenocarcinoma that are not suitable for local treatments, and to explore the predictive value of baseline serum vascular endothelial growth factor (VEGF) for the treatment. We retrospectively reviewed 14 consecutive patients, between Jan 2015 and Jul 2017, with brain metastases from lung adenocarcinoma who received bevacizumab and chemotherapy to determine efficacy and toxicity. Kaplan-Meier method was used to estimate survival curves, and univariate and multivariate analyses were performed by Cox proportional hazard model. The primary endpoints were objective response rate (ORR) and intracranial ORR (iORR). The secondary endpoints were progression-free survival (PFS), intracranial PFS (iPFS), overall survival (OS) and disease control rate (DCR). The efficacy of 12 patient was evaluated. Overall ORR was 25% (3/12) and the iORR of brain lesions was 33.3% (4/12). DCR was 75% (9/12). The median OS was 18.3 months, the median PFS was 6.7 months, and the median iPFS was 12 months. After 2 cycles of bevacizumab, 10 patients showed improved symptoms of central nervous system (CNS), and the symptom control rate was 83.3% (10/12). Head MRI showed that edema in the brain was greatly reduced in 6 patients, resulting in the lessened usage of dexamethasone. iPFS was significantly shorter in high VEGF group (3.6 vs. 8.0 m, P=0.02), and multivariate analysis showed a significant correlation between iPFS and serum baseline VEGF level (P=0.023). The most commonly adverse events of bevacizumab included leukopenia [5 (35.7%)], fatigue [3 (21.4%)], thrombocytopenia [3 (21.4%)], anemia [2 (14.3%)], which were mostly degree I and II. This study showed bevacizumab combined with chemotherapy could effectively control intracranial lesions, relieve symptoms, and improve the quality of life and survival of patients with brain metastases from lung adenocarcinoma. Serum baseline VEGF may be a predictor of efficacy of bevacizumab plus chemotherapy in the treatment of brain metastases from lung adenocarcinoma.

Vascular Endothelial Growth Factor (VEGF) on rabbit meniscus injury in the white-white zone expressed higher blood vessels distribution and type 1 collagen bridging post meniscal suturing

Background: Meniscus injury can occur in red - red zone with good prognostic as well as in white - white zone with bad one. General treatment of meniscus injury in white – white is menisectomy. It will destroy the articular surface of the knee joint cartilage. Administration the Vascular Endothelial Growth Factor (VEGF) will increase the proliferation of endothelial cells, fibroblast cells, collagen fibers type 1, and good prognostic for the healing of meniscus injury in white – white zone. Aim: The study aims to explore the effect of VEGF on rabbit meniscus injury. Methods: This research implemented an experimental study with randomized post-test control group design which used 38 male New Zealand Rabbits. There were two groups (18 rabbits as a control group and 18 rabbits as treatment one). They were adapted for one week, then control group had a sharp incision and sutured in white – white zone meniscus only, and treatment group had administration VEGF after done a sharp incision and sutured in white – white zone meniscus. In the next three weeks, all rabbits have been euthanized and then examined the meniscus for the expression of blood vessels distribution and the bridging of collagen type 1 by histopathology and immunohistochemistry examination. Results: The average median number for blood vessels distribution after administration VEGF in the sutured white-white zone was about 11.00 (interquartile range 2.00) and without VEGF was about 5.00 (interquartile range 1.00). In the treatment group with VEGF, 18 rabbits (100%) showed bridging collagen type 1, and the control one showed in 6 rabbits (33.33%). An inferential test for blood vessels distribution in white – white zone meniscus between treatment group with VEGF and control group without VEGF was significantly different (p=0.000). Analysis for bridging collagen type 1 between treatment group with VEGF and control group without VEGF showed significant differences (p=0.000). Conclusion: Administration VEGF on rabbit meniscus injury in the post suturing white-white zone expressed higher blood vessels distribution and bridging collagen type 1 compared with suturing only without VEGF.

Vascular endothelial growth factor for the treatment of femoral head osteonecrosis: An experimental study in canines.

AIMTo evaluate the treatment of osteonecrosis of the femoral head (ONFH) with the use of vascular endothelial growth factor (VEGF).METHODSIn 30 mature beagles (6 groups of 5 beagles) ONFH was induced cryosurgically and one of the following solutions was administered locally in the femoral head (FH) in each group: Single injection of 500 μg VEGF (t-VEGFμ group); single injection of 500 ng VEGF (t-VEGFn group); continuous delivery of 500 μg VEGF through osmotic micropump (t-VEGFpump-μ group); continuous delivery of 500 ng VEGF through osmotic micropump (t-VEGFpump-n group); single injection of 0.9% sodium chloride (t-NS group), while one group that served as control group did not receive any local solution (No-t group). FHs were retrieved 12 wk postoperatively, underwent decalcification and hematoxylin/eosin and toluidine blue staining. In two canines per group, one half of FH was processed without decalcification and stained with modified Masson Trichrome. Histological sections were observed by light microscopy and measured with a semi-automatized bone histomorphometry system and Bone Volume/Total Volume (BV/TV), Marrow Volume/Total Volume (MaV/TV), and Trabecular Thickness (TbTh) were assessed. Standard and robust tests (Welch, Brown Forsythe) of analysis of variance along with multiple comparisons, were carried out among the categories.RESULTSThe untreated (No-t) group had signs of osteonecrosis, whereas the VEGF groups revealed reversal of the osteonecrosis. Statistical analysis of the decalcified specimens revealed a significantly better BV/TV ratio and a higher TbTh between the VEGF treatment groups (except the t-VEGFn group) and the No-t group or the control t-NS group. Single dose 500 μgVEGF group had significantly better BV/TV ratio and higher TbTh when compared to the No-t group (50.45 ± 6.18 vs 29.50 ± 12.27, P = 0.002 and 151.44 ± 19.07 vs 107.77 ± 35.15, P = 0.161 respectively) and the control t-NS group (50.45 ± 6.18 vs 30.9 ± 6.67, P = 0.004 and 151.44 ± 19.07 vs 107.14 ± 35.71, P = 0.151 respectively). Similar differences were found for the prolonged VEGF delivery/pump groups of 500 μg and 500 ng. Analysis of the totality of specimens (decalcified/non-decalcified) enhanced the aforementioned differences and additionally revealed significant differences in the comparison of the TbTh.CONCLUSIONIn an experimental model of ONFH in canines it was found that local treatment with VEGF leads to bone tissue remodeling and new bone formation.

Electroacupuncture Combined with Intracerebral Injection of VEGF Improves Neurological Dysfunction Possibly by Down-regulating Expression of Endoplasmic Reticulum Stress Related Proteins ATF 6, etc. in Cerebral Ischemia-reperfusion Injury Rats

To observe the effect of electroacupuncture (EA) and EA combined with intracerebral injection of vascular endothelial growth factor (VEGF) on endoplasmic reticulum stress (ERS) related proteins and genes as activating transcription factor (ATF 6), inositol requiring enzyme-1 (IRE 1), CCAAT/enhancer binding protein homologous protein (CHOP), X box-binding protein-1 (XBP 1) of cerebral ischemia reperfusion injury (CIRI) rats, so as to study its repair effect for CIRI. Forty male SD rats were equally and randomly divided into 5 groups: sham operation, model, EA, VEGF and EA+VEGF groups (n=8). The CIRI model was established by occlusion of the middle cerebral artery (MCAO) with thread embolism method. For rats of the sham operation group, the right common carotid artery was isolated without MCAO. EA (2 Hz/100 Hz, 1-3 mA) was applied to "Baihui" (GV 20), left "Quchi" (LI 11) and left "Zusanli" (ST 36) for 30 min, once a day for 14 days. For rats of the VEGF and EA+VEGF groups, 10 µL VEGF (0.025 µg/µL) was injected into the lateral ventricle 24 h after successful modeling. The rats' neurological function was assessed by using the modified neurological severity score (mNSS), and the histopathological changes of cerebral tissue were observed by Nissl staining method. The expression levels of ERS related proteins and genes ATF 6, IRE 1, XBP 1 and CHOP were determined by western blot (WB) and fluorescent quantitative PCR, separately. After modeling, the level of mNSS was significantly higher in the model group than in the sham operation group (P<0.05), and the number of Nissl bodies was markedly lower in the model group than in the sham operation group (P<0.05). Following the treatment, the mNSS was significantly lower in the EA, VEGF and EA+VEGF groups than in the model group (P<0.05), and the numbers of Nissl bodies were obviously higher in the EA, VEGF and EA+VEGF groups than in the model group (P<0.05), suggesting an improvement of neurological dysfunction and a repair of the injured cerebral tissue after the treatment. The levels of CIRI-induced increase of mNSS and CIRI-induced decrease of the number of Nissl bodies in the EA+VEGF group were respectively remarkably lower or higher than those of the simple EA and simple VEGF groups (P<0.05). WB and PCR showed that the expression levels of ATF 6, IRE 1, XBP1 and CHOP proteins and genes were notably higher in the model group than in the sham operation group (P<0.05), and considerably lower in the EA, VEGF and EA+VEGF groups than in the model group (P<0.05). Comparison among the three treatment groups showed that after the treatment, the expression levels of ATF 6, IRE 1, XBP1 and CHOP proteins and genes were obviously lower in the EA+VEGF group than in the EA and VEGF groups (P<0.05). EA and EA plus intracerebral microinjection of VEGF can improve neurological function and promote cerebral tissue repair in CIRI rats, which is associated with their effects in down-regulating the expression of ERS related proteins ATF 6, IRE 1, XBP1 and CHOP. The effect of EA+VEGF is superior to that of simple EA and simple VEGF.