Vascular Endothelial Growth Inhibitor Research Articles

Angiogenic and anti-angiogenic factors during the post-hatching growth of the quail (Coturnix coturnix japonica) spleen.

Vascular endothelial growth factor (VEGF) family members are responsible for endothelial cells' growth, proliferation, migration, angiogenesis, vascular permeability, and differentiation and proliferation of non-endothelial cell types. VEGF and its receptors are found in mammalian lymphoid organs. The present study was conceived to determine (a) the presence and localization of angiogenic VEGF and its receptors (Fms-like tyrosine kinase 1 [Flt1/fms], fetal liver kinase 1 [Flk1]/kinase insert domain receptor [KDR], Fms-like tyrosine kinase 4 [Flt4]) and vascular endothelial growth inhibitor (VEGI) in the quail spleen; and (b) whether their expressions in the spleen components change during the post-hatching growth of the organ, using immunohistochemistry. Immunohistochemical stainings showed that VEGI, VEGF, and VEGF receptors were expressed in many components, including the vascular endothelial and smooth muscle cells, ellipsoid-associated cells (EACs), and immune cells, of quail spleen and that VEGF and its receptors' immunostaining intensity scores (ISs) varied depending on the post-hatching growth period, while VEGI-IS did not change. In addition, ISs of VEGI, VEGF, Flt1/fms, and Flt4 in EACs were weak to moderate, while flk1/KDR-IS in EACs adjacent to the capsule of Schweigger-Seidel sheaths (ellipsoids) was higher than other proteins, supports a more important and specific role of Flk1/KDR in the EAC function. These specific expressions of VEGI, VEGF, flt1/fms, flk1/KDR, and flt4 proteins in splenic cell types suggest their particular roles, in the functional development of splenic components and thus, are critical to post-hatching maturation of quail spleen. These findings indicate that the expression levels of VEGF, Flt1/fms, and Flt4, except Flk1/KDR, are low in the quail spleen, and only a few components of the spleen express VEGF, Flt1/fms, and Flt4 under normal conditions.

The Relation of VEGFA, VEGFR2, VEGI, and HIF1A Genetic Variants and Their Serum Protein Levels with Breast Cancer in Egyptian Patients.

Breast cancer is the most common type of cancer in Egyptian females. Polymorphisms in the angiogenesis pathway have been implicated previously in cancer risk and prognosis. The aim of the current study was to determine whether certain polymorphisms in the genes of vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor 2 (VEGFR2), vascular endothelial growth inhibitor (VEGI), and hypoxia-inducible factor-1α (HIF1A) associated with breast cancer development. The study included 154 breast cancer patients and 132 apparently healthy age-matched females as a control group. VEGFA rs25648 genotyping was performed using (ARMS) PCR technique; while VEGFR2 rs2071559, VEGI rs6478106, and HIF-1α rs11549465 were genotyped by the PCR-RFLP method. Serum levels of VEGF, VEGFR2, VEGI, and HIF1A proteins in breast cancer patients and controls were measured by ELISA. There was a significant association between the VEGFA rs25648 C allele and breast cancer risk (OR 2.5, 95% CI 1.7-3.6, p < 0.001). VEGFA rs25648 C/C genotype was statistically significantly higher in breast cancer patients vs. control (p < 0.001). Participants with the T/T and T/C VEGFR2 rs2071559 genotypes had 5.46 and 5 higher odds, respectively, of having breast cancer than those with the C/C genotype. For the VEGI rs6478106 polymorphism, there was a higher proportion of C allele in breast cancer patients vs. control (p = 0.003). Moreover, the C/C genotype of VEGI rs6478106 was statistically significantly higher in breast cancer patients vs. control (p = 0.001). There was no significant difference in genotypes and allele frequencies of HIF1A rs11549465 polymorphism between breast cancer cases and control individuals (p > 0.05). Serum levels of VEGFA, VEGI, and HIF1A were considerably greater in women with breast cancer than in the control (p < 0.001). In conclusion, the genetic variants VEGFA rs25648, VEGFR2 rs2071559, and VEGI rs6478106 revealed a significant association with increased breast cancer risk in Egyptian patients.

Dual-targeted and dual-sensitive self-assembled protein nanocarrier delivering hVEGI-192 for triple-negative breast cancer

Breast cancer is a highly prevalent malignancy worldwide among women with an increasing incidence in recent years. Triple-negative breast cancer (TNBC), a specific type of breast cancer, occurs primarily in young women and exhibits large tumor size, high clinical stage, and extremely poor prognosis with a high rate of lymph node, liver, and lung metastases. TNBC is insensitive to endocrine therapy and trastuzumab treatment, and there is an urgent need for effective therapeutics and treatment guidelines. However, investigations into antiangiogenic agents for the treatment of TNBC are ongoing. In this study, we successfully engineered a self-assembled protein nanocarrier TfRBP9-hVEGI-192-ELP fusion protein (TVEFP) to deliver the therapeutic protein, human vascular endothelial growth inhibitor (hVEGI-192). This was found to be effective in inhibiting tumor angiogenesis in vivo. The protein nanocarrier effectively inhibited the progression of TNBC in vivo and showed the behavior of self-assembly, thermoresponsiveness, enzyme stimulation-responsiveness, tumor-targeting, biocompatibility, and biodegradability. Near-infrared imaging studies showed that fluorescent dye-stained TVEFP effectively aggregated at the tumor site. The TVEFP nanocarrier significantly expands the application of the therapeutic protein hVEGI-192 and improves the imaging and biotherapeutic effects in TNBC, chiefly based on anti-angiogenesis effects.

Bevacizumab Arrests Osteoarthritis Progression in a Rabbit Model: A Dose-Escalation Study.

Cartilage neoangiogenesis holds a prominent role in osteoarthritis (OA) pathogenesis. This study aimed to assess the efficacy bevacizumab, an antibody against vascular endothelial growth factor and inhibitor of angiogenesis, in a rabbit OA model. Animals were divided into four groups: one receiving a sham intra-articular knee injection and three groups undergoing 5, 10, and 20 mg intra-articular bevacizumab injections. The effect of the antibody on articular cartilage and synovium was assessed through histology and quantified with the Osteoarthritis Research Society International (OARSI) scores. Immunohistochemistry was performed to investigate type 2 collagen, aggrecan, and matrix metalloproteinase 13 (MMP-13) expression. Bevacizumab treatment led to a significant reduction of cartilage degeneration and synovial OA changes. Immunohistochemistry revealed significantly lower cartilage MMP-13 expression levels in all experimental groups, with the one receiving 20 mg bevacizumab showing the lowest. The antibody also resulted in increased production of aggrecan and type 2 collagen after administration of 5, 10, and 20 mg. The group treated with 20 mg showed the highest levels of type 2 collagen, while aggrecan content was even higher than in the healthy cartilage. Intra-articular bevacizumab has been demonstrated to effectively arrest OA progression in our model, with 20 mg being the most efficacious dose.

A Protective Role of Tumor Necrosis Factor Superfamily-15 in Intracerebral Hemorrhage-Induced Secondary Brain Injury.

Destabilization of blood vessels by the activities of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) following intracerebral hemorrhage (ICH) has been considered the main causes of aggravated secondary brain injury. Here, we show that tumor necrosis factor superfamily-15 (TNFSF15; also known as vascular endothelial growth inhibitor), an inhibitor of VEGF-induced vascular hyper-permeability, when overexpressed in transgenic mice, exhibits a neuroprotective function post-ICH. In this study, we set-up a collagenase-induced ICH model with TNFSF15-transgenic mice and their transgene-negative littermates. We observed less lesion volume and neural function perturbations, together with less severe secondary injuries in the acute phase that are associated with brain edema and inflammation, including vascular permeability, oxidative stress, microglia/macrophage activation and neutrophil infiltration, and neuron degeneration, in the TNFSF15 group compared with the littermate group. Additionally, we show that there is an inhibition of VEGF-induced elevation of MMP-9 in the perihematomal blood vessels of the TNFSF15 mice following ICH, concomitant with enhanced pericyte coverage of the perihematomal blood vessels. These findings are consistent with the view that TNFSF15 may have a potential as a therapeutic agent for the treatment of secondary injuries in the early phase of ICH.

VEGI downregulation is correlated with nodal metastasis and poor prognosis in lung adenocarcinoma.

Although the incidence of lung cancer is increasing worldwide, the molecular mechanisms for its tumorigenesis, progression and prognosis remain unknown. As a member of the tumor necrosis factor superfamily, vascular endothelial growth inhibitor (VEGI) is involved in the development and progression of many malignant diseases. In the present study, the expression of VEGI and CD31 was examined via immunohistochemistry in non-small cell lung cancer (NSCLC) tissues obtained from 150 patients with NSCLC. The inhibitory effect of VEGI on tumor-associated blood vessel formation and growth was investigated by determining the relationship between VEGI protein expression and microvascular density (MVD). Prognostic significance was evaluated using the Kaplan-Meier method. VEGI expression was downregulated or lost in 68.7% (103/150) of patients with NSCLC, an effect that was more prevalent in adenocarcinoma (AC), 76.0% (57/75), than in squamous cell carcinoma, 61.3% (46/75). A significant negative correlation was indentified between VEGI expression and lymphovascular invasion (P=0.039) and lymph node metastasis (P=0.017) in AC tissue. Additionally, MVD was significantly lower in the VEGI-rich group compared with the VEGI-poor group. The downregulation of VEGI expression was also associated with poorer overall survival (P=0.011) in patients with AC. The present study therefore provides evidence that VEGI may be a new and effective prognostic marker of lung AC.

TL1A inhibits atherosclerosis in apoE-deficient mice by regulating the phenotype of vascular smooth muscle cells

TNF ligand-related molecule 1A (TL1A) is a vascular endothelial growth inhibitor to reduce neovascularization. Lack of apoE a expression results in hypercholesterolemia and atherosclerosis. In this study, we determined the precise effects of TL1A on the development of atherosclerosis and the underlying mechanisms in apoE-deficient mice. After 12 weeks of pro-atherogenic high-fat diet feeding and TL1A treatment, mouse aorta, serum, and liver samples were collected and used to assess atherosclerotic lesions, fatty liver, and expression of related molecules. We found that TL1A treatment significantly reduced lesions and enhanced plaque stability. Mechanistically, TL1A inhibited formation of foam cells derived from vascular smooth muscle cells (VSMCs) but not macrophages by activating expression of ABC transporter A1 (ABCA1), ABCG1, and cholesterol efflux in a liver X receptor-dependent manner. TL1A reduced the transformation of VSMCs from contractile phenotype into synthetic phenotypes by activating expression of contractile marker α smooth muscle actin and inhibiting expression of synthetic marker osteopontin, or osteoblast-like phenotype by reducing calcification. In addition, TL1A ameliorated high-fat diet-induced lipid metabolic disorders in the liver. Taken together, our work shows that TL1A can inhibit the development of atherosclerosis by regulating VSMC/foam cell formation and switch of VSMC phenotypes and suggests further investigation of its potential for atherosclerosis treatment.

VEGI Improves Outcomes in the Early Phase of Experimental Traumatic Brain Injury

Excessive expression of vascular endothelial growth factor (VEGF) is a common cause of blood–brain barrier (BBB) breakdown that triggers severe complications following traumatic brain injury (TBI). It has been shown that inhibition of VEGF activities may attenuate cerebral edema in pathological conditions. Vascular endothelial growth inhibitor (VEGI; also known as TNFSF15), a cytokine produced largely by vascular endothelial cells, is capable of downregulating VEGF expression and inhibiting VEGF receptor-2 (VEGFR2) activation. In this study we found that TBI can cause breakdown of BBB and sharp increases of VEGF/VEGI and Angpt2/Angpt1 ratios in the injured tissues. VEGI treatment resulted in a marked decrease of BBB permeability and concomitant restoration of normal ratios of VEGF/VEGI and Angpt2/Angpt1. Consistently, alleviated edema, decreased neuron cell death, and improved neurological functions were observed when the experimental animals were treated with VEGI in the early phase of TBI. Our findings suggest that administration of VEGI recombinant protein at early phases of TBI is beneficial to stabilization of the disease conditions.

Inhibition of intracranial hemangioma growth and hemorrhage by TNFSF15.

Hemangioblastoma (HB) is an abnormal intracranial buildup of blood vessels that exhibit a great potential for hemorrhage. Surgical options are limited, and few medications are available for treatment. We show here by immunohistochemical analysis that HB lesions display highly increased levels of VEGF expression and macrophage/microglia infiltration compared with those in normal brain tissues. In the meantime, TNF superfamily 15 (TNFSF15) (also known as vascular endothelial growth inhibitor), an antiangiogenic cytokine, is highly expressed in normal brain blood vessels but diminished in HB lesions. We set up a brain hemangioma model by using mouse bEnd.3 cells of a T antigen-transformed endothelial cell line that produce a large amount of VEGF. When implanted in mouse brains, these cells form lesions that closely resemble the pathologic characteristics of HB. Retroviral infection of bEnd.3 cells with TNFSF15 leads to inhibition of VEGF production and retardation of hemangioma formation. Similar results are obtained when wild-type bEnd.3 cells are implanted in the brains of transgenic mice overexpressing TNFSF15. Additionally, TNFSF15 treatment results in enhanced pericyte coverage of the blood vessels in the lesions together with reduced inflammatory cell infiltration and decreased hemorrhage. These findings indicate that the ability of TNFSF15 to counterbalance the abnormally highly angiogenic and inflammatory potential of the microenvironment of HB is of therapeutic value for the treatment of this disease.-Yang, G.-L., Han, Z., Xiong, J., Wang, S., Wei, H., Qin, T.-T., Xiao, H., Liu, Y., Xu, L.-X., Qi, J.-W., Zhang, Z.-S., Jiang, R., Zhang, J., Li, L.-Y. Inhibition of intracranial hemangioma growth and hemorrhage by TNFSF15.

Epigenetic modulators hydralazine and sodium valproate act synergistically in VEGI-mediated anti-angiogenesis and VEGF interference in human osteosarcoma and vascular endothelial cells

Vascular endothelial growth inhibitor (VEGI; also referred to as TNFSF15 or TL1A) is involved in the modulation of vascular homeostasis. VEGI is known to operate via two receptors: Death receptor‑3 (DR3) and decoy receptor‑3 (DcR3). DR3, which is thus far the only known functional receptor for VEGI, contains a death domain and induces cell apoptosis. DcR3 is secreted as a soluble protein and antagonizes VEGI/DR3 interaction. Overexpression of DcR3 and downregulation of VEGI have been detected in a number of cancers. The aim of the present study was to investigate the effects of sodium valproate (VPA), a histone deacetylase inhibitor, in combination with hydralazine hydrochloride(Hy), a DNA methylation inhibitor, on the expression of VEGI and its related receptors in human osteosarcoma(OS) cell lines and human microvascular endothelial(HMVE) cells. Combination treatment with Hy and VPA synergistically induced the expression of VEGI and DR3 in both OS and HMVE cells, without inducing DcR3 secretion. In addition, it was observed that the combination of VPA and Hy significantly enhanced the inhibitory effect on vascular tube formation by VEGI/DR3 autocrine and paracrine pathways. Furthermore, the VEGI/VEGF‑A immune complex was pulled down by immunoprecipitation. Taken together, these findings suggest that DNA methyltransferase and histone deacetylase inhibitors not only have the potential to induce the re‑expression of tumor suppressor genes in cancer cells, but also exert anti‑angiogenic effects, via enhancement of the VEGI/DR3 pathway and VEGI/VEGF‑A interference.

Distinct Expression Patterns of Two Tumor Necrosis Factor Superfamily Member 15 Gene Isoforms in Human Colon Cancer

BackgroundTumor necrosis factor superfamily member 15 (TNFSF15) gene is involved in development of several cancers. It encodes two proteins: tumor necrosis factor ligand-related molecule 1A (TL1A) and vascular endothelial growth inhibitor 192 (VEGI-192). The main receptor for TL1A is death receptor 3 (DR3).AimsWe investigated expression of TL1A, VEGI-192, and DR3 transcripts in different stages of colon cancer and compared them with survival of patients. We also aimed to reveal possible effects of microsatellite instability (MSI) and selected TNFSF15 single-nucleotide polymorphisms (SNPs) on expression of this gene.MethodsForty-five healthy individuals and 95 colon cancer patients were included in the study. Expression of VEGI-192, TL1A, and DR3 was measured by quantitative PCR. SNP and MSI analyses were performed on DNA isolated from normal or cancer tissue.ResultsExpression of VEGI-192 and TL1A was elevated in colon cancer, although the level of VEGI-192 decreased, while the level of TL1A increased with the progression of cancer. Patients with low expression of TL1A and/or high expression of VEGI-192 in tumor-transformed tissue showed longer survival. DR3 expression was decreased in the cancer, but it did not change with the tumor progression. Alleles T of rs6478108 and G of rs6478109 SNPs were associated with elevated expression of the TNFSF15 gene. There was no relation between the MSI status and TNFSF15 expression levels.ConclusionsExpression of the TNFSF15 gene isoforms was associated with the progression of colon cancer. Levels of TL1A and VEGI-192 transcripts can be considered as independent prognostic factors for colon cancer.

VEGI174 protein and its functional domain peptides exert antitumour effects on renal cell carcinoma.

Vascular endothelial growth inhibitor (VEGI) has been identified as an anti‑angiogenic cytokine. However, the effects of VEGI174 protein, and its functional domain peptidesV7andV8, on renal cell carcinoma (RCC) remain unknown. In the present study, the protein and peptides were biosynthesised as experimental agents. The A498 and 786‑O RCC cell lines, and an established mouse xenograft model, were separately treated with VEGI174, V7orV8. Cellular functions, including proliferation, migration and invasion, were subsequently detected. Cell migration and invasion were monitored using the xCELLigence system. Furthermore, tumour growth and mouse behaviours, including mobility, appetite and body weight, were assessed. The results demonstrated that VEGI174, V7 and V8 inhibited the proliferation, migration and invasion of A498 and 786‑O cell lines when administered at concentrations of 1and100pM, 10nM and 1µM. The inhibitory effects exhibited dose‑ and time‑dependent antitumour activity. Furthermore, VEGI174, V7andV8 inhibited tumour growth in A498 and 786‑O xenograft mice. In the A498 xenografts, the tumour growth inhibition (TGI) rates in the VEGI174‑, V7‑andV8‑treated groups were71, 20and31%, respectively. In the 786‑O xenografts, the TGI rates in the VEGI174‑, V7‑andV8‑treated groups were34, 26and31%, respectively. There was no significant loss in body weight and no cases of mortality were observed for all treated mice. In conclusion, VEGI174, V7 and V8 exhibited potential antitumour effects and were well tolerated invivo. V7andV8, as functional domain peptides of the VEGI174 protein, may be studied for the future treatment of RCC.

Vascular Endothelial Growth Inhibitor, a Cytokine of the Tumor Necrosis Factor Family, is Associated With Epithelial-Mesenchymal Transition in Renal Cell Carcinoma.

Previous studies have revealed that the activation of the epithelial-mesenchymal transition (EMT) endows metastatic properties upon cancer cells to promote invasion and migration. In this study, immunohistochemical analysis was performed in 50 cases of clear cell renal cell carcinoma (RCC) and paired normal kidney tissues. We detected the expression of vascular endothelial growth inhibitor (VEGI) and EMT markers (E-cadherin, fibronectin, and Slug) and recorded the clinical, pathologic, and follow-up (median follow-up: 79.0 mo) information. The expression of VEGI and E-cadherin was significantly lower in RCC tissues compared with normal kidney tissues (P<0.001). However, the expression of fibronectin and Slug was higher in RCC tissues (P<0.05). VEGI and EMT marker expression marginally differed in tumor size and stage. Significant differences were found in the pathologic grade (P<0.05). The Spearman correlation analysis suggested a positive correlation between VEGI and E-cadherin (r=0.451, P<0.01). A negative correlation was shown between VEGI and fibronectin (r=-0.465, P<0.01). There was also a negative correlation between VEGI and Slug (r=-0.758, P<0.01). During the 79.0 months (range, 7 to 119 mo) of follow-up, 6 patients died due to RCC, and the tumor-free survival rate was 88% (44/50). We did not find a significant correlation between VEGI/EMT markers (E-cadherin, fibronectin, and Slug) and overall survival (P>0.05). Our findings indicate that VEGI plays an important role in EMT in RCC. It suggests that VEGI may be investigated as a disease biomarker and therapeutic target in RCC.

Topical dimethyl sulfoxide inhibits corneal neovascularization and stimulates corneal repair in rabbits following acid burn

Neovascularization of the cornea is characterized by the growth of blood vessels caused by imbalances between angiogenic and anti-angiogenic factors. We investigated whether the expression of Vascular endothelial growth factor (VEGF), Vascular endothelial growth factor receptor (VEGF), Vascular endothelial growth inhibitor (VEGI) receptors, as well as topical drug treatments, participate in regulating corneal neovascularization after corneal damage and remodeling. We used 72 mature male New Zealand rabbits. Corneal burns were induced by hydrofluoric acid under general anesthesia. The rabbits then were treated with indomethacin or dimethyl sulfoxide (DMSO). The animals were euthanized on days 2, 7 and 14 after injury. Each cornea was fixed with 10% neutral formalin. On days 2, 7 and 14, VEGF, flk1/KDR and flt1/fms were strongly expressed in the epithelial, stromal and inflammatory cells, but not in the corneal endothelial cells. On day 7, newly formed blood vessels were observed growing toward the center of the cornea. In the control, indomethacin treated, DMSO–treated, and indomethacin + DMSO–treated animals, VEGI, VEGF, and the receptors, flk1/KDR, flt1/fms and flt4, were expressed at different densities in the neovascular regions. This was particularly evident in the indomethacin- and indomethacin + DMSO–treated groups on days 7 and 14, compared to day 2. Treatment with VEGF and DMSO stimulated repair of corneal damage. We suggest that VEGI in the endothelial cells of neovascularized cornea may act as a signaling protein that promotes balance between cell proliferation and apoptosis. Topical administration of DMSO inhibited corneal neovascularization more effectively than indomethacin.

Trophic and neurotrophic factors in human pituitary adenomas (Review).

The pituitary gland is an organ that functionally connects the hypothalamus with the peripheral organs. The pituitary gland is an important regulator of body homeostasis during development, stress, and other processes. Pituitary adenomas are a group of tumors arising from the pituitary gland: they may be subdivided in functional or non-functional, depending on their hormonal activity. Some trophic and neurotrophic factors seem to play a key role in the development and maintenance of the pituitary function and in the regulation of hypothalamo-pituitary-adrenocortical axis activity. Several lines of evidence suggest that trophic and neurotrophic factors may be involved in pituitary function, thus suggesting a possible role of the trophic and neurotrophic factors in the normal development of pituitary gland and in the progression of pituitary adenomas. Additional studies might be necessary to better explain the biological role of these molecules in the development and progression of this type of tumor. In this review, in light of the available literature, data on the following neurotrophic factors are discussed: ciliary neurotrophic factor (CNTF), transforming growth factorsβ(TGF‑β), glial cell line-derived neurotrophic factor(GDNF), nerve growth factor(NGF), vascular endothelial growth factor (VEGF), vascular endothelial growth inhibitor (VEGI), fibroblast growth factors (FGFs) and epidermal growth factor (EGF) which influence the proliferation and growth of pituitary adenomas.

Identification of Novel Proteins Interacting with Vascular Endothelial Growth Inhibitor 174 in Renal Cell Carcinoma.

Vascular endothelial growth inhibitor (VEGI) is a multipotential cytokine that plays a role in regulating immunity, anti-angiogenesis, and inhibiting tumor growth. However, the proteins that interact with it are still unknown. In the present study, we examined the proteins that interact with VEGI174 and their expression in renal cell carcinoma (RCC). The proteins that interact with VEGI174 were identified using western blot, pull-down assay, and mass spectrometry. The expressions of VEGI174 and the interacting proteins were examined in RCC and were compared to normal renal tissues using immunohistochemical staining and RNA-seq respectively. The results of the mass spectrometric analysis showed that ACLY, ENO1, ZIK1, AKR1C3, and MYC may interact with VEGI174. When compared to the TCGA database, the expression level of VEGI174 in RCC was lower than that in normal kidney using RNAseq (p<0.001). The expression levels of ACLY, ENO1, ZIK1, AKR1C3 and MYC in RCC were higher than those in normal kidney (p<0.05, all of above factors). Moreover, immunochemical staining results also showed that the expression levels of AKR1C3 in RCC were significantly higher those that in normal kidney (p<0.001) and was also positively correlated with higher RCC stage and grade. Taken together, our findings showed that VEGI174 may interact with ACLY, ENO1, ZIK1, AKR1C3, and MYC. The expression of ACLY, ENO1, AKR1C3 and MYC is increased in RCC. AKR1C3 was a new factor that may correlate with the progression of RCC. The results indicated that VEGI174 has more functions than we currently know in the development and progression of RCC.

Protein of Vascular Endothelial Growth Inhibitor 174 Inhibits Epithelial–Mesenchymal Transition in Renal Cell Carcinoma In Vivo

Vascular endothelial growth inhibitor (VEGI) is a member of the tumor necrosis factor superfamily, identified as an anti-angiogenic cytokine. However, the effect of VEGI on epithelial-mesenchymal transition (EMT) in renal cell carcinoma (RCC) is still unknown. In this study, protein VEGI174 was designed and synthesized. Renal cell carcinoma A498 cells were implanted into immune-deficient mice to establish tumor models. Two groups were included: control group treated with saline, and VEGI174-treated group. Data of tumor growth were collected every 3 to 4 days. Two weeks later, the tumor specimens were harvested for immunohistochemical staining of EMT markers (E-cadherin, N-cadherin, vimentin). Compared to the saline-treated group, the VEGI174-treated group showed significant inhibition of tumor growth (p<0.05). The expression of E-cadherin was significantly higher in the VEGI174-treated group compared to the saline-treated group (p<0.01). However, the expression of N-cadherin and vimentin were reduced in the VEGI174-treated group. Our findings indicate that VEGI174 prevents progression and tumor metastasis through inhibiting EMT in RCC in vivo. This may provide a new approach for the treatment of RCC.

Vascular endothelial growth inhibitor 174 and its functional domains inhibit epithelial-mesenchymal transition in renal cell carcinoma cells invitro.

The present study was carried out to investigate the effects of vascular endothelial growth inhibitor174 (VEGI174) and its functional domains (V7andV8) on epithelial‑mesenchymal transition (EMT) in renal cell carcinoma (RCC) cells invitro. The RCC cell lines A498 and 786‑O were used in this study. Based on our preliminary study, we selected full‑length VEGI174 and its functional domains (V7 and V8) as the target genes in this study. Plasmids containing VEGI174, V7 or V8 transgenes were constructed and transfected into A498 and 786‑O cell lines. Cytological activity was tested during cell culture. Quantitative PCR and western blot analysis were performed to determine the expression levels of EMT markers (E‑cadherin, vimentin, β‑catenin and Slug). Overexpression of VEGI174, V7 or V8 did not have a significant influence on cell viability (P>0.05). The mRNA level of E‑cadherin was significantly upregulated, while that of vimentin was downregulated in A498VEGIexp, A498V7exp, A498V8exp, 786‑OVEGIexp, 786‑OV7exp and 786‑OV8exp cells compared with the cells containing the empty plasmid controls (P<0.05). The western blot results showed that changes in protein expression levels were consistent with the changes in mRNA expression. Both the mRNA and protein expression levels of β‑catenin and Slug were downregulated in the A498VEGIexp, A498V7exp, A498V8exp, 786‑OVEGIexp, 786‑OV7exp and 786‑OV8exp cells. In conclusion, overexpression of VEGI174, V7 or V8 inhibited EMT in A498 and 786‑O cells. Notably, V7 and V8 are two effective functional domains of VEGI174 that have the potential to be studied for peptide synthesis and the treatment of RCC.

Changes in TL1A levels and associated cytokines during pathogenesis of diabetic retinopathy

Tumor necrosis factor (TNF) ligand related molecule 1A (TL1A), also termed TNF superfamily member 15 and vascular endothelial growth inhibitor is important for tumorigenicity and autoimmunity. However, the function of TL1A in diabetic retinopathy (DR) remains to be elucidated. The present study established a diabetes mellitus (DM) rat model to investigate TL1A, vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) expression levels in the retina, vitreous and serum of rats with DM at different stages (1 month group, 3 month group and 6 month group). The present study determined that TL1A expression levels in the retina and vitreous from the DM 1 month group were significantly lower compared with the control group. However, TL1A levels in the retina and vitreous were significantly increased in advanced stages of DM compared with the control group. Furthermore, the levels of VEGF in the retina and vitreous were significantly higher in the DM groups compared with the control group. The expression levels of TNF-α and IL-1β in the retina and vitreous were significantly higher in DM 3 month and 6 month groups compared with the control group. It is of note that the expression levels of TL1A were significantly lower in the DM 1 and 3 month groups compared with the control group; however, they were significantly increased in the DM 6 month group compared with the DM 3 month group. The expression levels of VEGF, TNF-α and IL-1β in blood serum have been observed to exhibit similar expression change dynamics as those of the retina and vitreous. Therefore, these findings suggest that TL1A may be a protective factor of DR, and may provide a rationale for the development of novel therapeutic strategies to treat DR.

The role of vascular endothelial growth factor and vascular endothelial growth inhibitor in clinical outcome of traumatic brain injury

ObjectivesTumor necrosis factor superfamily-15 (TNFSF15) also known as vascular endothelial growth inhibitor (VEGI) is a cytokine that modulates anti-angiogenesis and inflammation. Vascular endothelial growth factor (VEGF) promotes angiogenesis and vascular permeability following traumatic brain injury (TBI). The balance of VEGF and VEGI may play a key role in the maintenance of vascular and immune system homeostasis in the brain. However, the dynamic changes of circulating VEGF and VEGI after traumatic brain injury (TBI) and the correlation between plasma VEGF and plasma VEGI remains obscure. In this study, we were to investigate whether circulating VEGF and VEGI can be used as prognostic markers for patients with TBI. Patients and methodsA prospective clinical study was conducted in two neurosurgical intensive care units of Tianjin Medical University General Hospital and Tianjin Huanhu Hospital (Tianjin, China). 40 patients and 30 healthy controls were recruited. The recruited subjects were aged over 18 with randomized gender and GCS. 1mL of blood was withdrawn on 1, 4, 7, 14, and 21days after TBI. Blood samples were centrifuged at 3000rpm and the supernatants were used to measure VEGF and VEGI by ELISA kit. Results1) Circulating VEGF in TBI patients was decreased on the 1st day after TBI, then climbed up on the 4th day, reaching a maximum level on the14th day after TBI, as compared to normal controls. VEGF level returned to normal level on 21th day after TBI. 2) Circulating VEGI in TBI patients was decreased on the 1st and 4th day after TBI, then climbed up on the 7th day after TBI, reaching a maximum level on 14th day after TBI, as compared to normal controls. VEGI levels declined to normal level on 21th day after TBI. 3) There was a significant positive correlation between circulating VEGF and VEGI. 4) However, TBI patients whose conditions had improved exhibited lower VEGF levels 7days after TBI when compared to TBI patients whose condition had deteriorated. Survivors exhibited higher VEGI levels 7days after TBI when compared to non-survivors. 5)TBI patients whose condition had improved exhibited higher VEGI levels when compared to TBI patients whose condition had deteriorated 21days after TBI. Patients with mild TBI exhibited higher VEGI levels than those with moderate and severe TBI 21days after TBI. 6) A lower rate of recovery and higher hospital mortality were found in patients with VEGF/VEGI ratio≥2.366 as compared to those with VEGF/VEGI ratio<2.366 7days after TBI. Conclusions1) VEGF level positively correlates with VEGI after TBI. 2) The elevation of VEGF exhibits an adverse effect from 4 to 14days after TBI while it has an advantageous effect from 14 to 21days after TBI. Increasing VEGI levels are beneficial in recovery after TBI. Controlling the ratio of VEGF/VEGI may benefit the clinical outcome following TBI.