Vascular Endothelial Growth Inhibitor Research Articles

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 The recruited subjects were aged over 18 with randomized gender and GCS. 1mL of blood was withdrawn on 1, 4, 7, 14, and 21days after TBI.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.

Evaluation of (188)Re-labeled NGR-VEGI protein for radioimaging and radiotherapy in mice bearing human fibrosarcoma HT-1080 xenografts.

Vascular endothelial growth inhibitor (VEGI) is an anti-angiogenic protein, which includes three isoforms: VEGI-174, VEGI-192, and VEGI-251. The NGR (asparagine-glycine-arginine)-containing peptides can specifically bind to CD13 (Aminopeptidase N) receptor which is overexpressed in angiogenic blood vessels and tumor cells. In this study, a novel NGR-VEGI fusion protein was prepared and labeled with (188)Re for radioimaging and radiotherapy in mice bearing human fibrosarcoma HT-1080 xenografts. Single photon emission computerized tomography (SPECT) imaging results revealed that (188)Re-NGR-VEGI exhibits good tumor-to-background contrast in CD13-positive HT-1080 tumor xenografts. The CD13 specificity of (188)Re-NGR-VEGI was further verified by significant reduction of tumor uptake in HT-1080 tumor xenografts with co-injection of the non-radiolabeled NGR-VEGI protein. The biodistribution results demonstrated good tumor-to-muscle ratio (4.98 ± 0.25) of (188)Re-NGR-VEGI at 24h, which is consistent with the results from SPECT imaging. For radiotherapy, 18.5MBq of (188)Re-NGR-VEGI showed excellent tumor inhibition effect in HT-1080 tumor xenografts with no observable toxicity, which was confirmed by the tumor size change and hematoxylin and eosin (H&E) staining of major mouse organs. In conclusion, these data demonstrated that (188)Re-NGR-VEGI has the potential as a theranostic agent for CD13-targeted tumor imaging and therapy.

Functional roles of angiogenic factors and receptors on non-endothelial cells in the oropharyngeal cavity of the chukar partridge (Alectoris chukar)

The vascular endothelial growth factor (VEGF) family belong to the platelet-derived growth factor supergene family and is involved in angiogenesis and mitogenesis. The VEGF–VEGFR system regulates endothelial cell proliferation, migration, vascular permeability, secretion and other non-endothelial cells functions. To clarify the possible role of endothelial and non-endothelial cells, VEGF and its receptors, vascular endothelial cell growth inhibitor (VEGI) were immunohistochemically examined in oropharyngeal organs. Ten adult partridges were used in this study and the pharynx and larynx were dissected together with the palate and tongue. VEGI, VEGF and its receptor were highly expressed in luminal epithelial and stromal cells, when compared to glandular epithelial and muscle cells (P < 0.05). Moreover, VEGF, its receptors and VEGI were expressed rather strongly in the endothelial cells of the blood capillaries and in both the endothelial and smooth muscle cells of the large and small blood vessels. In conclusion, VEGF and its receptors (flt1/fms, flk1/KDR and flt4) and VEGI were expressed by various cell groups at varying intensity in the oropharyngeal organs. This demonstrates that they play a critical role in the regulation and maintenance of the functions in cells different from endothelial ones as well as in cell proliferation, differentiation, apoptosis and angiogenesis.

A case-control study about the association between vascular endothelial growth inhibitor gene polymorphisms and breast cancer risk in female patients in Northeast China.

Objective The inhibition of the neovascularization in tumors is a potential therapeutic target of cancer. Vascular endothelial growth inhibitor (VEGI) is a member of the TNF superfamily which has the ability to suppress the formation of new vessels in tumors. In order to study the association between VEGI gene polymorphisms and breast cancer risk, a case-control study was conducted in Chinese Han women in Northeast China. Methods Our study involved 708 female breast cancer patients and 685 healthy volunteers. Four SNPs of VEGI gene were analyzed through the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The association between VEGI gene polymorphisms and breast cancer risk was analyzed in our study. The relation between VEGI gene variants and clinical features of breast cancer including lymph node (LN) metastasis, estrogen receptor (ER), progestrogen receptor (PR), tumor protein 53 (p53), human epidermal growth factor receptor 2 (Her-2) and triple negative (ER-/PR-/Her-2-) status was analyzed as well.Results We found that the CT genotype and T allele of rs6478106 were more frequent in patients than in controls. There was also a statistical difference in the distribution of Crs6478106Grs4263839 haplotype between patients and controls. In addition, SNP rs6478106 and rs4979462 were related with the Her-2 status. Conclusions Our results suggest that VEGI gene variants may be related to the breast cancer risk and the clinical features of breast cancer in Chinese Han women in Northeast China.

Physiological roles of the angiogenic factors during posthatching development period and adults in the quail lung

AbstractThe bronchus and vasculature form an intrinsic functional component of the avian lung, and its growth must be tightly regulated and coordinated by lung epithelial and endothelial development. Vascular endothelial growth inhibitor (VEGI), vascular endothelial growth factor (VEGF) and its receptors (flk1/KDR, flt1/fms, flt4) are required for epithelial and endothelial cell survival and apoptosis. Especially, VEGF and its receptors are critical for the development of the lung and serve as a maintenance factor during adult life. To determine the function of VEGI, VEGF and its receptors in the posthatching lung development, we revealed its expression and localization using by immunohistochemical procedure. VEGI, VEGF and its receptors were observed in the structural components of the bronchi, atria and air capillaries, as well as in the pulmonary blood vessels throughout the posthatching development period. On the other hand, immunostaining for VEGI, VEGF and its receptors was faintly detected in the glands of the secondary bronchi. Furthermore, it was determined that the secondary bronchial and atrial muscles did not display VEGF immunoreactions. Our results showed that VEGF and its receptors (flt1/fms, flk1/KDR and flt4) and VEGI were expressed at varying intensity by different cell groups. Therefore, they are also required for the development of the lung component during posthatching period.

VEGI attenuates the inflammatory injury and disruption of blood–brain barrier partly by suppressing the TLR4/NF-κB signaling pathway in experimental traumatic brain injury

Acute traumatic brain injury (TBI) tends to cause the over-activation of inflammatory response and disruption of blood brain barrier (BBB), associating with long-term cognitive and behavioral dysfunction. Vascular endothelial growth inhibitor (VEGI), as a suppressor in the angiogenesis specifically by inducing apoptosis in proliferating endothelial cells, has been applied to different diseases, especially the tumors. But rare study had been done in the field of brain injury. So in this study, we investigated the effects and mechanisms associated with VEGI-induced neuroprotection following CNS injury in mice TBI models. We demonstrated that the VEGI treatment reduced the contusion brain tissue loss, the permeation of inflammatory cells (MPO+) and the activation of microglia (Iba-1+). The treatment up-regulated the tight junction proteins (CLN5, ZO-1 and OCLN), which are vital importance for the integrity of the blood brain barrier (BBB), the B-cell lymphoma 2 (Bcl-2) cell survival factors, while down-regulated the expression of TLR4, NF-κB and inflammatory cytokines (IL-1β, TNF-α, iNOS). The treatment also decreased the expression of reactive astrocytes (GFAP+), as well as the VEGF, and lowered the permeability of Evens Blue (EB). These findings suggested that the VEGI-treatment could alleviate the post-traumatic excessive inflammatory response, and maintain the stability of blood vessels, remitting the secondary brain damage.

Expression of vascular endothelial growth factor receptors and their ligands in rat uterus during the postpartum involution period

Vascular endothelial growth factor (VEGF) and its specific receptors, FLt1/fms, Flk1/KDR and FLt4, play important roles in vasculogenesis, and physiological and pathological angiogenesis. Whether angiogenic growth factors are involved in regulating angiogenic processes during the postpartum involution period (PP) of the rat uterus is unknown. We used immunohistochemistry to analyze the expression levels of VEGF, the fms-like tyrosine kinase 1 (FLt1/fms), the kinase insert domain-containing region 1 (Flk1/KDR), Fms-related tyrosine kinase 4 (FLt4) and vascular endothelial growth inhibitor (VEGI) in the rat uterus during the days 1, 3, 5, 10 and 15 of the PP to determine the temporal and spatial expressions of VEGF and its receptors during the PP. Throughout the PP, cytoplasmic and membrane staining of VEGI, VEGF and their receptors were observed in the lumens, crypts and glandular epithelial cells as well as in connective tissue and vascular endothelial and smooth muscle cells in the endometrium. We found that the intensity of the immunoreactions in the endometrium varied with the morphological changes that occurred during involution. Immunoreactions for VEGI, VEGF and their receptor, Flk1/KDR, in the luminal epithelial cells were stronger than those in the glandular epithelial and stromal cells, particularly during PP 1, 3 and 5, which suggests that these peptides may contribute to re-epithelialization of the endometrium. On the other hand, Flt1/fms immunoreactivity was strong mainly in the stromal cells during the PP. The presence of VEGF and its receptors (FLt1/fms, Flk1/KDR, FLt4) in the stromal cells and blood vessels during the PP suggests that they may contribute to regulating stromal repair and angiogenesis in the involuting uterus of the rat.

Sodium valproate, a histone deacetylase inhibitor, modulates the vascular endothelial growth inhibitor-mediated cell death in human osteosarcoma and vascular endothelial cells.

The level of vascular endothelial growth inhibitor (VEGI) has been reported to be negatively associated with neovascularization in malignant tumors. The soluble form of VEGI is a potent anti-angiogenic factor due to its effects in inhibiting endothelial cell proliferation. This inhibition is mediated by death receptor 3 (DR3), which contains a death domain in its cytoplasmic tail capable of inducing apoptosis that can be subsequently blocked by decoy receptor 3 (DcR3). We investigated the effects of sodium valproate (VPA) and trichostatin A (TSA), histone deacetylase inhibitors, on the expression of VEGI and its related receptors in human osteosarcoma (OS) cell lines and human microvascular endothelial (HMVE) cells. Consequently, treatment with VPA and TSA increased the VEGI and DR3 expression levels without inducing DcR3 production in the OS cell lines. In contrast, the effect on the HMVE cells was limited, with no evidence of growth inhibition or an increase in the DR3 and DcR3 expression. However, VPA-induced soluble VEGI in the OS cell culture medium markedly inhibited the vascular tube formation of HMVE cells, while VEGI overexpression resulted in enhanced OS cell death. Taken together, the HDAC inhibitor has anti-angiogenesis and antitumor activities that mediate soluble VEGI/DR3-induced apoptosis via both autocrine and paracrine pathways. This study indicates that the HDAC inhibitor may be exploited as a therapeutic strategy modulating the soluble VEGI/DR3 pathway in osteosarcoma patients.

Effect of atorvastatin on diabetic rat endothelial cells and retinal lesions.

We investigated the effect of atorvastatin on vascular endothelial growth inhibitor (VEGI) expression in rats with diabetic retinopathy. Wistar rats were divided into a blank group and diabetic model group, which was further randomly divided into treatment and control groups. Rats in the treatment group received 10 mg/kg atorvastatin daily, while rats in the blank and control groups received normal saline. Rats were randomly euthanized at 3 or 6 months. Immunohistochemical staining was used to determine changes in VEGI and vascular endothelial growth factor, interleukin-4, and tumor necrosis factor α levels in rats with diabetic retinopathy. Survival rate in the treatment group was 84% (63/75) after 6 months, which was significantly higher than that in the control group (P < 0.05); rats in the control group showed the lowest survival rate. Survival in the treatment group was higher than that in the control group but not significant compared with the blank group after 3 months. VEGI, vascular endothelial growth factor, tumor necrosis factor α, and interluekin-4 expression was lower than that in the control group, but higher than the blank group after 3 months. The expression of each factor decreased to the blank group level in the treatment group and was significantly lower than that in the control group after 6 months (P < 0.05). Expression in control and blank groups was similar at 3 and 6 months. Atorvastatin can inhibit VEGI and vascular endothelial growth factor expression to protect rats from diabetic retinopathy.

Single nucleotide polymorphisms in vascular endothelial growth inhibitor and its association with development and metastasis of children's neuroblastoma

Objective To identify functional single nucleotide polymorphisms(SNPs) in the promoter region of vascular endothelial growth inhibitor(VEGI) gene and to explore the relationship between these SNPs and the development and metastasis of children's neuroblastoma. Methods A case-control study was performed using PCR-restriction fragment length polymorphism(PCR-RFLP) assay in 126 patients with neuroblastoma and 196 healthy children to detect the genotype-358 T>C, -638 A>G of VEGI promoter region.The association between SNPs of VEGI and neuroblastoma in children was analyzed by using Logistic regression model.Odds ratios(OR) and 95% confidence intervals(CI) were estimated by using Logistic regression. Results Two SNPs, VEGI-358T>C and -638A>G located upstream the translation start site were identified associating with Logistic regression analysis showed that subjects carrying the VEGI-358CC and-638GG genotype played an important role of tumor malignancy in children(Ⅱstage, OR=10.667, 95%CI 1.387-82.033, P=0.023; Ⅲstage, OR=5.333, 95%CI 0.968-29.393, P=0.055; Ⅳstage, OR=4.606, 95%CI 1.007-21.072, P=0.049). The VEGI -638GG genotype significantly increased the risk of tumor malignancy in children, and the result was the same as VEGI -358CC. Conclusions These findings indicate that functional genetic variants in VEGI -358T>C and -638A>G may play an important role in neuroblastoma progression in children.VEGI -358CC and -638GG carriers have higher risk of proliferation and metastasis of neuroblastoma. Key words: Neuroblastoma; Vascular endothelial growth inhibitor; Single nucleotide polymorphisms; Metastasis

Vascular endothelial growth inhibitor affects the invasion, apoptosis and vascularisation in breast cancer cell line MDA-MB-231

Background Breast cancer is one of the most common malignant female diseases worldwide. It is a significant threat to every woman’s health. Vascular endothelial growth inhibitor (VEGI) is known to be abundant in endothelial cells. According to previous literature, overexpression of VEGI has been shown to inhibit tumor neovascularisation and progression in cellular and animal models, but there has been limited research on the significance of VEGI in the breast cancer. Methods In our study, cell lines MDA-MB-231 were first constructed in which VEGI mediated by lentivirus over-expressed. The effects of VEGI over-expression on MDA-MB-231 cells were investigated both in vitro and in vivo. The expression of VEGI in the MDA-MB-231 cells after infection of lentivirus was analyzed using real-time PCR and Western blotting. The effect of the biological characteristics of MDA-MB-231 cells was assessed by growth, invasion, adhesion, and migration assay with subcutaneous tumor-bearing nude mice models. Then the growth curves of the subcutaneous tumors were studied. Expressions of VEGI, CD31 and CD34 in the tumors were analyzed by immunohistochemistry and apoptosis was detected by flow cytometry and immunohistochemistry. Results Infection of MDA-MB-231 cells within the lentivirus resulted in approximately a 1 000-fold increase in the expression of VEGI. As can be seen in the invasion, adhesion and migration assay, the over-expression of VEGI can inhibit the ability of MDA-MB-231 cells during migration, adhesion and invasion. The volume of the subcutaneous tumor in the over-expression group was distinctly and significantly less than that of the control groups. Immunohistochemistry analysis of the tumor biopsies clearly showed the expression of VEGI in the over-expression group increased while CD31 and CD34 decreased significantly. In vitro and in vivo, the early apoptosis rate and the apoptosis index were increased within the VEGI over-expression group as compared with the control group. Conclusions Taken together, recombinant lentivirus that were successfully constructed, demonstrated up-regulated VEGI gene expression in breast cancer cells. Lentivirus-mediated over-expression of VEGI weakened the ability of the breast cancer cell migration, adhesion and invasion. Over-expression of VEGI diminished the tumorigenic capacity of breast cancer cells in vivo. Up-regulation of VEGI gene expression however inhibited breast cancer MDA-MB-231 cell in the early apoptosis.

VEGF and Id-1 in pancreatic adenocarcinoma: Prognostic significance and impact on angiogenesis

ObjectivesThe significance of vascular endothelial growth factor (VEGF) and inhibitor of differentiation/DNA synthesis (Id-1) in tumor neoangiogenesis and tumor progression in pancreatic ductal adenocarcinoma (PDAC) is still unclear. Given the central role of VEGF in cancer angiogenesis and the inconclusive results on Id-1 expression in PDAC, it is of great interest to investigate whether Id-1 and VEGF expression are associated with angiogenesis and prognosis in PDAC. MethodsParaffin-embedded specimens from 60 consecutive patients with PDAC were immunostained for VEGF, Id-1 and CD34 and staining quantification was assessed by Image analysis system. The correlations among the expression of individual angiogenic factors and microvessel density (MVD), clinicopathologic features and clinical prognosis were analyzed. ResultsId-1 and VEGF Positive Activity Indices (PAIs) closely correlated with each other. MVD positively correlated with both Id-1 and VEGF expression. More advanced T and N status correlated with more intense expression of Id-1, VEGF and higher MVD. With regard to prognostic significance higher Id-1 PAI (adjusted HR = 1.69, 95%CI: 1.10–2.59, p = 0.017), higher VEGF PAI (adjusted HR = 2.66, 95%CI: 1.09–6.50, p = 0.032), and MVD (adjusted HR = 1.55, 95%CI: 1.27–1.88, p < 0.001) were associated with poorer survival. ConclusionsVEGF and Id-1 overexpression were found to be associated with high MVD and emerged as adverse prognostic factors in terms of patient survival in PDAC. The potential of selective anti-angiogenic targeting therapy for pancreatic malignancies should prompt further validation of the present findings in studies encompassing larger samples and more elaborate techniques.

Expression and function of vascular endothelial growth inhibitor in aged porcine bladder detrusor muscle cells

Aging of the bladder detrusor muscle plays an important role in lower urinary tract symptoms in elderly people. Our previous work demonstrated that elderly patients have increased levels of vascular endothelial growth inhibitor (VEGI) in bladder tissue. Therefore, we hypothesized that VEGI may play a role in aging of the bladder detrusor muscle cells. This study aims to develop and characterize primary cultures of aged porcine bladder detrusor muscle cells in order to explore the expression and function of VEGI. Bladder samples from female pigs were divided into two groups: the aged group (Model) and the young group (Control). We confirmed β-galactosidase expression, a marker for senescence, in aged muscle cells (identified by α-smooth muscle actin (α-SMA) staining), but not in the young group. mRNA levels of VEGI-251 and death receptor 3 (DR3) were up-regulated (P<0.05) and total cell protein levels of VEGI-251, DR3 and nuclear factor-kappa B [NF-κB (p65)], membrane protein levels of DR3, and nuclear protein levels of NF-κB (p65) were significantly higher (P<0.01) in the Model cells compared to Control cells. In conclusion, we have established a method to culture aged detrusor muscle cells derived from porcine bladder. Higher levels of VEGI-251, DR3 and NF-κB (p65) were observed in the aged cells. VEGI-251 may function by increasing DR3 on cellular membranes and promoting the transfer of NF-κB into the nucleus. This suggests that VEGI may be a target for reversing the aging process of bladder detrusor muscle cells.

Immunolocalization of vascular endothelial growth factor, its receptors (flt1/fms, flk1/KDR, flt4) and vascular endothelial growth inhibitor in the bitch uterus during the sexual cycle

Angiogenesis is regulated by proangiogenic and antiangiogenic factors. Vascular endothelial growth factor (VEGF) is a prime proangiogenic regulator, whereas vascular endothelial growth inhibitor (VEGI) is a specific antiangiogenic cytokine. To clarify temporal changes in the localization of pro-angiogenic and anti-angiogenic factors in the uterus of normal bitches during the proestrus, estrus, diestrus and anestrus phases of the estrous cycle, the expressions of VEGF and its receptors (flt1/fms, flk1/KDR and flt4) and their correlation with VEGI were analyzed using immunohistochemistry. Uteruses were collected after ovariohysterectomy. Immunohistochemical staining was evaluated semi-quantitatively by an immunohistochemical total score consisting of the sum of the intensity and proportional scores. The results in the bitch uterus demonstrated that positive immunohistochemical staining was found exclusively in the cytoplasm and apical membrane of luminal and glandular epithelial, stromal and smooth muscle cells and nuclear staining was observed in the flt1/fms, flk4 and VEGI during proestrous and estrous. Semi-quantitative analyses revealed that the total score for VEGF in the glandular epithelial cells was significantly higher than that of luminal, endometrial stromal and myometrial smooth muscle cells during proestrous (p<0.05). The total score for flk1/KDR and flt4 in the glandular epithelium was also significantly higher than that of endometrial stromal cells during proestrous, whilst the total score for flt1/fms in the glandular epithelium was significantly higher than that of endometrial stromal cells during anestrus (p<0.05). We conclude that, in the bitch uterus, cyclic changes may be precisely regulated by the combined functions of VEGF family members, angiogenic VEGF and VEGF receptors, and the angiogenesis inhibitor VEGI.

AB0081 Effect of chondroitin sulfate on the factors involved in synovial inflammation

BackgroundChondroitin sulfate (CS), an interesting candidate for the therapeutic treatment of osteoarthritis (OA), has been shown in clinical trials to reduce swelling and effusion in knee OA.ObjectivesWe thus aimed to...

AB0067 Chondroitin sulfate regulates two anti-angiogenic factors in human osteoarthritic synovial fibroblasts

BackgroundThe symptomatic slow acting drug for osteoarthritis (SYSADOA), chondroitin sulfate, has attracted much interest as a biological agent for its use in the effective relief of disease symptoms. This is...

Suppression of renal cell carcinoma growth in vivo by forced expression of vascular endothelial growth inhibitor

Vascular endothelial growth inhibitor (VEGI) has been associated with tumor-related vasculature in certain malignancies. However, its implication in renal cell carcinoma (RCC), an angiogenesis-dependent tumor, remains unknown. In the present study, we investigated the role played by VEGI in RCC. The expression of VEGI was examined in human renal tissue and RCC cell lines using immunohistochemical staining and RT-PCR, respectively. The biological impact of modifying the expression of VEGI in RCC cells was evaluated using in vitro and in vivo models. We show that VEGI mRNA is expressed in a wide variety of human RCC cell lines, all of normal renal and most of RCC tissue specimens. VEGI protein expression was observed in normal renal tubular epithelial cells, but was decreased or absent in RCC specimens, particularly in tumors with high grade. Moreover, forced expression of VEGI led to an inhibition of vascular endothelial tube formation, decrease in the motility and adhesion of RCC cells in vitro. Interestingly, forced expression of VEGI had no bearing on growth, apoptosis and invasive capacity of RCC cells. However, tumor growth was reduced in xenograft models. Immunohistochemical staining showed that microvessel density decreased in VEGI forced expression xenograft tumor samples. Taken together, our findings showed that the expression of VEGI is decreased in RCC, particularly in tumors with higher grade. Together with its inhibitory effect on cellular motility, adhesion, vascular endothelial tube formation and tumor growth in vivo, this suggests that VEGI functions mainly through inhibition of angiogenesis and is a negative regulator of aggressiveness during the development and progression of RCC.

Expression and role of vascular endothelial growth inhibitor in sporadic clear cell renal cell carcinoma

To evaluate the expression of vascular endothelial growth inhibitor (VEGI) in sporadic clear cell renal cell carcinoma (CCRCC) and explore its relationships between VEGI expression, pathologic grade and tumor staging. Western blot and immunohistochemical staining were used to detect the expression of VEGI in CCRCC cell line (786-O cells), CCRCC and paired normal kidney tissues. A total of 50 CCRCC cases were recruited. There were 37 males and 13 females with an average age of 53 ± 12 years. The tumor sizes were < 7 cm (n = 33) and ≥ 7 cm (n = 17). Their pathologic grades were G1 (n = 14), G2 (n = 22) and G3 (n = 14) and pathologic stages pT1 (n = 32), 10 pT2 (n = 10) and pT3 (n = 8). VEGI protein was predominantly located in cytoplasm. Compared with normal kidney tissues(mean optic density (MOD) of VEGI staining: 0.40 ± 0.16), it was lower in CCRCC tissues (MOD: 0.11 ± 0.06, P < 0.01). In addition, the positive rate of VEGI expression, the expression intensity and the MOD of VEGI protein were negatively correlated with the pathologic grade of CCRCC (r = -0.640, P < 0.01; r = -0.831, P < 0.01; r = -0.781, P < 0.01 respectively). The MOD of VEGI expression in ≥ 7 cm tumors (MOD, 0.08 ± 0.04) was significantly lower than that in < 7 cm tumors (MOD: 0.12 ± 0.06, P < 0.05). However, there was no correlations between the VEGI protein level and age, gender and pathologic stage of patients (P > 0.05). VEGI protein is predominantly located in cytoplasm. Compared with CCRCC tissues, VEGI protein level is higher in normal ones. In consideration of negative correlations between VEGI expression, pathologic grade and tumor size, it is implied that VEGI may play a negative regulatory role in the occurrence and development of CCRCC.

The distrubution of vascular endothelial growth factor and its receptors (flk1/fms, flk1/KDR, flt4) as well as vascular endothelial growth inhibitor in the canine uterus during the sexual cycle

The distrubution of vascular endothelial growth factor and its receptors (flk1/fms, flk1/KDR, flt4) as well as vascular endothelial growth inhibitor in the canine uterus during the sexual cycle

Expression of death receptor-3 in human breast cancer and its functional effects on breast cancer cells in vitro

Death receptor-3 (DR3) plays controversial roles in cancer. Currently, DR3 is known to be a functional receptor of vascular endothelial growth inhibitor (VEGI). The role of DR3 in breast cancer remains unclear. The present study investigated DR3 expression in a clinical cohort of breast cancer patients and its role in breast cancer cells invitro. The expression of DR3 was examined in a breast cancer cohort using quantitative PCR (Q-PCR) and immunohistochemistry (IHC) in comparison to the patients' data. In vitro function of DR3 was examined through the targeting of this molecule in MCF7 and MDA-MB-231 breast cancer cells using ribozyme transgene technology. Decreased DR3 expression was noted in breast cancer tissues compared to normal tissues and decreased expression of DR3 was generally associated with a poorer prognosis as well as a significantly shorter long-term survival (p=0.038). Targeting of DR3 invitro in breast cancer cell lines resulted in impaired migratory rates compared to respective control cells. Collectively, these data suggest a complex role for DR3 in breast cancer development and progression.