BACKGROUND: Distraction osteogenesis (DO) is a useful method for treating cases demanding the generation of new bone. During DO, the angiogenic activity is crucial factor in the new bone formation. The aim of this study was to detect the autocrine growth activity in the cellular components of the distracted bone with observation of the co-expression of vascular endothelial growth factor (VEGF) and its receptors following the mandibular DO. MATERIALS AND METHODS: Unilateral mandibular distraction (0.5 mm twice per day for 10 days) was performed in six mongrel dogs. Two animals were killed at 7, 14, and 28 days after completion of distraction, respectively. Immediately after the animals were killed, the right mandibles were harvested en block. Immunohistochemical staining was processed for observation of the VEGF expression, and double immunofluorescent staining was also processed for detection of the co-expression of osteocalcin and VEGF's two distinct receptors (VEGFR-1 and VEGFR-2). RESULTS: At 7 and 14 days after distraction, the expressions of VEGF were significantly increased in the osteogenic cells of the distracted bone. Up to 28 days after distraction, VEGF was still expressed moderate in the osteoblastic cells of distracted bone. The co-expressions of osteocalcin / VEGFR-1 and osteocalcin / VEGFR-2 were observed in the distracted bone at 7 and 14 days after distraction. In the double immunofluorescent staining, the co-expression's level of osteocalcin / VEGFR-1 was more than that of osteocalcin / VEGFR-2. Conclusion: Taken together, this study suggested that VEGF plays an important role in the osteogenesis, and these osteoblastic cell-derived VEGF might act as autocrine growth factor during distraction osteogenesis. In the other word, the cellular components, such as osteoblasts and immature fibroblast-like cellsor mesenchymal cells in the distracted bone, might have autocrine growth activity during distraction osteogenesis.
Animals ; Dogs ; Mandible ; Osteoblasts ; Osteocalcin ; Osteogenesis ; Osteogenesis, Distraction* ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factor Receptor-1 ; Vascular Endothelial Growth Factor Receptor-2

OBJECTIVES: Vascular endothelial growth factor(VEGF), one of potent cytokines, and its receptors were related with various biological functions and pathological conditions. The purpose of this study was to investigate the changes of serum level of free VEGF, soluble VEGFR-1, and soluble VEGFR-2 after treatment with atypical antipsychotic drug in schizophrenia. METHOD: The schizophrenic patients were diagnosed with DSM-IV and were prospectively followed up for 4 and 8 weeks. Thirteen schizophrenic patients were evaluated their clinical assessment with serum levels of free VEGF, sVEGFR-1, sVEGFR-2, and positive and negative symptom scale(PANSS) at baseline, 4 weeks, and 8 weeks after treatment with atypical antipsychotic drug. Thirteen normal control subjects were recruited and matched with the patient group by age and sex. RESULT: The serum level of free VEGF(295.2+/-43.7pg/ml)and sVEGFR-2(8259+/-336.7) at baseline(before treatment) in schizophrenic patients were not significantly different, compared with the control group(199.0+/-28.8 and 8481+/-371.9) respectively. However, the serum level of sVEGFR-1(86.2+/-10.3, p<0.05) was significantly increased in the schizophrenic patients compared with the control group(59.0+/-6.4). After treatment with antipsychotic drug, the serum levels of free VEGF at 4 weeks(338.9+/-56.5) and 8 weeks(309.5+/-58.7) were not significantly, different compared with baseline. But the serum levels of sVEGFR-1 was significantly decreased at 8 weeks(57.3+/-6.3, p<0.05) after antipsychotic drug treatment. The serum levels of sVEGFR-2 were decreased at 4 weeks(7761+/-403.0, p<0.05) and 8 weeks(7435+/-333.5, p<0.05) compared with baseline. CONCLUSION: The decreased serum level of sVEGFR-1 and sVEGFR-2 might be affected by dopaminergic system which was influenced by antipsychotic drug.
Cytokines ; Diagnostic and Statistical Manual of Mental Disorders ; Dopamine ; Humans ; Prospective Studies ; Schizophrenia* ; Vascular Endothelial Growth Factor A* ; Vascular Endothelial Growth Factor Receptor-1 ; Vascular Endothelial Growth Factor Receptor-2

The study was to investigate the expression of VEGFA, VEGFC, angiopoietin-1, angiopoietin-2 and their receptors on yolk sac blood island, AGM region during gestation of 3th-12th weeks of human embryo. Human embryo contingently aborted at 3 - 12 weeks of gestation were collected with signed agreements of the pregnant women suffered from accidental abortions. The specimens were fixed by 4% paraformaldehyde and embedded by paraffin. 5 micro m serial sections were made. HE and immunohistochemistry method (SABC) and light-microscope were employed. The results showed that VEGFA and its receptors flt1/flk-1, VEGFC and its receptor flt-4, angiopoietin-2 and its receptor tie-2 proteins were expressed strongly and angiopoietin-1 was weakly expressed by hematopoietic cells and vascular endothelial cells of blood island at 21 and 25 days of gestation. In the 4th week of gestation, immuno-positive reaction of these factors and their receptors appeared in the aorta and mesonephros deposited in larger, rounded and nucleated cells which represented hematopoietic cells. Up to 7th week, positive hematopoietic cells in the regions were much abundant. The number of positive cells decreased at 8th week. Up to 12th week, almost all blood cells were immuno-negative. VEGFA, flt-1, flt-4, angiopoietin-1, angiopoietin-2 and Tie-2 protein were expressed mainly by gonad at 6 - 8 weeks, but it did not express VEGFC and flk-1. The immuno-reaction of the factors and their receptors could not detected in vascular endothelial cells during 3-12th weeks of gestation. It is concluded that hematopoietic cells and endothelial cells in blood island of yolk sac, mesonephros and dorsal aorta co-expressed some factors and their receptors in relation to vasculogenesis and hematopoiesis. Intraembryonic hematopoiesis began in the 4th week of gestation.
Angiopoietin-1 ; analysis ; Angiopoietin-2 ; analysis ; Embryo, Mammalian ; chemistry ; Extracellular Matrix Proteins ; analysis ; Humans ; Immunohistochemistry ; Receptor, TIE-2 ; analysis ; Receptors, Vascular Endothelial Growth Factor ; analysis ; Vascular Endothelial Growth Factor A ; analysis ; Vascular Endothelial Growth Factor C ; analysis ; Vascular Endothelial Growth Factor Receptor-1 ; Vascular Endothelial Growth Factor Receptor-2 ; analysis ; Vascular Endothelial Growth Factor Receptor-3 ; analysis ; Yolk Sac ; chemistry

Vascular endothelial growth factor (VEGF) exerts its biological functions by its specific VEGF receptors (VEGFRs), which includes VEGFR-1, VEGFR-2, VEGFR-3, neuropilin-1 and neuropilin-2. These VEGF receptors not only distribute in endothelial cells, but also in epidermal keratinocytes. VEGFRs may play a significant role in pathogenesis of the epidermal neoplasm and the VEGF-VEGFR signaling pathway may be a novel therapy target for neoplasm derived from epidermis.
Animals ; Epidermis ; metabolism ; Humans ; Neoplasms ; metabolism ; Neuropilins ; genetics ; metabolism ; Receptors, Vascular Endothelial Growth Factor ; genetics ; metabolism ; Vascular Endothelial Growth Factor Receptor-1 ; genetics ; metabolism ; Vascular Endothelial Growth Factor Receptor-2 ; genetics ; metabolism ; Vascular Endothelial Growth Factor Receptor-3 ; genetics ; metabolism

PURPOSE: The aim of this study was to determine the effect of alcohol on the expression of VEGF-A, PEDF, and VEGFR-2 in human osteoblasts. MATERIALS AND METHODS: Human osteoblasts primarily derived from the intertrochanteric region of the femur with osteonecrosis and fracture (control) were cultured with alcohol (0, 20, 100, 150 mM). The level of cell proliferation and the expression levels of VEGF-A mRNA, PEDF mRNA, and VEGFR-2 mRNA was evaluated according to the alcohol concentrations and the culture periods. RESULTS: Osteoblasts with the added alcohol showed an early increase in cell population, and a subsequent decrease or steady level thereafter compared with those without alcohol (p<0.05). The osteoblasts in the osteonecrosis group showed an increase in VEGF-A mRNA and PEDF mRNA expression at high alcohol concentrations (100, 150 mM), resulting in an decreased VEGF-A/PEDF ratio, while those in the control group showed an increase in VEGF-A mRNA expression and a decrease in PEDF mRNA expression, resulting in an increase in the VEGF-A/PEDF ratio (p<0.05). CONCLUSION: Alcohol stops the proliferation of osteoblasts and can cause an imbalance between VEGF-A and PEDF, thereby inhibiting the neovascularization of osteonecrosis.
Cell Proliferation ; Femur ; Head* ; Humans ; Necrosis* ; Osteoblasts* ; Osteonecrosis ; RNA, Messenger ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factor Receptor-2*

This study was to evaluate the expression of vascular endothelial growth factor receptors (VEGFRs) in tumor and stromal cells of tougue squamous cell carcinoma (SCC). We also wanted to characterize the differences, from the angiogenic aspect, between cancer-associated stromal cells and non-malignant stromal cells. Paraffin-embedded tumor specimens from eleven patients with tongue SCCs were studied. Immunohistochemical staining for VEGFR-1,-2, and -3 was performed on the tumor cells, stromal fibroblasts and tumor-associated macrophages of the specimens. The expression of all 3 receptors was detected in the tumor cells themselves of the biopsy specimens. All 3 receptors were also expressed on stromal cells, except that VEGFR-2 was not expressed in stromal fibroblasts. In radical excision specimens, the staining intensity for VEGFR-1, -2 in the tumor cells and VEGFR-1,-3 in the tumor-associated macrophages was significantly lower than that in the biopsy specimens (P < 0.05). By using the general marker of fibroblast and macrophage, 5B5 and CD68, respectively, we performed double immunofluorescence staining for 5B5 and each VEGFR in the stromal fibroblasts and for CD68 and each VEGFR in the tumor-associated macrophages of the radical excision specimens. We used 4 cases of fibroma and 4 cases of chronic inflammation tissue as the controls. It was found that only each marker was expressed in the control group, however, 5B5/VEGFR-1 and 5B5/VEGFR-3 in the stromal fibroblasts, and CD68/VEGFR-1 and CD68/VEGFR-3 in the tumor-associated macrophages were double stained in the radical excision specimens. Although our study used small number of specimens, the results of our study showed that in tongue SCC, in association with the angiogenesis, the stromal cells showed the activated phenotype and this was different from the nonmalignant stromal cells.
Biopsy ; Carcinoma, Squamous Cell* ; Fibroblasts ; Fibroma ; Fluorescent Antibody Technique ; Humans ; Inflammation ; Macrophages ; Phenotype ; Receptors, Vascular Endothelial Growth Factor* ; Stromal Cells* ; Tongue* ; Vascular Endothelial Growth Factor A* ; Vascular Endothelial Growth Factor Receptor-1 ; Vascular Endothelial Growth Factor Receptor-2

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignant neoplasms and is a leading cause of mortality worldwide. Metastasis to the liver is a frequent event in patients with CRC. An essential step in the metastatic cascade is angiogenesis. METHODS: This study included 45 patients who underwent a partial colectomy with hepatic resection for CRC with hepatic metastases. Immunohistochemistry was performed using vascular endothelial growth factor (VEGF)-A, VEGF receptor (VEGFR)-1, VEGFR-2, and CD34 antibodies to examine the relationship between CRC with liver metastases and angiogenesis. RESULTS: CRC showed significantly stronger expression of VEGF-A, VEGFR-1, and VEGFR-2 than liver metastases (p < 0.05). Microvessel density was also higher in CRC than in liver metastases (p < 0.05). CONCLUSIONS: Compared with previous studies, we found a higher expression of VEGF-A, VEGFR-1, VEGFR-2, and microvessel density in CRC than in liver metastases, which could be ascribed to a difference in vessel distribution and blood supply in each organ. Given its profuse blood supply and distinct cell populations, the liver might provide a rich milieu for tumor cell growth with less expression of angiogenesis-inducing agents.
Antibodies ; Colectomy ; Colorectal Neoplasms ; Glycosaminoglycans ; Humans ; Immunohistochemistry ; Liver ; Microvessels ; Neoplasm Metastasis ; Receptors, Vascular Endothelial Growth Factor ; Thymus Gland ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factor Receptor-1 ; Vascular Endothelial Growth Factor Receptor-2 ; World Health Organization

Here, we investigated the role of zerumbone, a natural cyclic sesquiterpene of Zingiber zerumbet Smith, on angiogenesis using human umbilical vein endothelial cells (HUVECs). Zerumbone inhibited HUVECs proliferation, migration and tubule formation, as well as angiogenic activity by rat aorta explants. In particular, zerumbone inhibited phosphorylation of vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1, which are key regulators of endothelial cell function and angiogenesis. In vivo matrigel plug assay in mice demonstrated significant decrease in vascularization and hemoglobin content in the plugs from zerumbone-treated mice, compared with control mice. Overall, these results suggest that zerumbone inhibits various attributes of angiogenesis, which might contribute to its reported antitumor effects.
Animals ; Aorta ; Endothelial Cells ; Fibroblast Growth Factors ; Ginger* ; Human Umbilical Vein Endothelial Cells ; Mice ; Phosphorylation ; Rats ; Receptors, Vascular Endothelial Growth Factor ; Vascular Endothelial Growth Factor Receptor-2

growth factor(EGF) and activation of its receptor(EGFR) are associated with progressive growth of SCCHN. Vascular endothelial growth factor(VEGF) signaling molecules are related with neoangiogenesis and vascular metastasis of SCC. In this study, we determined the therapeutic effect of AEE788(Novartis Pharma AG, Basel, Switzerland), which is a dual inhibitor of EGFR/ErbB2 and VEGFR tyrosine kinases, on human oral SCC. At first, we screened the expression of EGFR, c-ErbB2(HER-2) and VEGFR-2 in a series of human oral SCC cell lines. And then we evaluated the effects of AEE788 on the phosphorylation of EGFR and VEGFR-2 in a oral SCC cell line expressing EGFR/HER-2 and VEGFR-2. We also evaluated the effects of AEE788 alone, or with paclitaxel(Taxol) on the oral SCC cell growth and apoptosis. As a result, all oral SCC cells expressed EGFR and VEGFR-2. Treatment of oral SCC cells with AEE788 led to dose-dependent inhibition of EGFR and VEGFR-2 phosphorylation, growth inhibition, and induction of apoptosis. Moreover, AEE788 sensitizes the cells to paclitaxel-mediated toxicity and apoptosis. These data mean EGFR and VEGFR-2 can be reliable targets for molecular therapy of oral SCC, and therefore warrant clinical use of EGFR/VEGFR inhibition in the treatment of patients with recurrent or metastatic oral SCC.]]>
Apoptosis ; Carcinoma, Squamous Cell ; Cell Line ; Epidermal Growth Factor ; Head ; Humans ; Neoplasm Metastasis ; Phosphorylation ; Phosphotransferases ; Receptor, Epidermal Growth Factor ; Receptors, Vascular Endothelial Growth Factor ; Survival Rate ; Tyrosine ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factor Receptor-2

Vandetanib (ZD6474, Zactima(TM)) is a novel, orally available inhibitor of different intracellular signaling pathways involved in tumor growth, progression, and angiogenesis, including vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and rearranged during transfection tyrosine kinase activity. The most frequently reported adverse events attributed to vandetanib include diarrhea, elevated aminotransferase, asymptomatic corrected QC interval prolongation, and hypertension. In a few randomized, double-blinded studies, cutaneous adverse events including these general symptoms have been reported, but there are only a few reports on the photosensitivity reaction to vandetanib domestically as conducted by dermatologists. In this report, we describe two cases of photosensitivity reactions induced by vandetanib. After improvement with steroid and antihistamine, the photosensitivity reaction was redeveloped by sequential treatment with docetaxel.
Diarrhea ; Hypertension ; Piperidines ; Protein-Tyrosine Kinases ; Quinazolines ; Receptor, Epidermal Growth Factor ; Taxoids ; Transfection ; Vascular Endothelial Growth Factor Receptor-2