• Development and Reproduction
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• v.17 no.1
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• pp.17-24
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• 2013

This study examined the expression of inhibitor of DNA-binding (Id) proteins and vascular endothelial growth factor (VEGF) in the ovary according to female age using a mice model as the first step in investigating the potential role of Ids and VEGF in ovarian aging. C57BL inbred female mice of three age groups (6-9, 14-16, and 23-26 weeks) were injected with 5 IU pregnant mare's serum gonadotropin (PMSG) in order to synchronize the estrus cycle. After 48 h, ovarian expression of Ids and VEGF was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR), western blot and immunohistochemistry. Ovarian apoptosis was examined by ovarian expression of Bcl-2 and Bcl-xL. Expression of Id-1 and VEGF was decreased with advancing female age, but not Id-2, Id-3, and Id-4. In particular, their expressions were significantly decreased in aged mice of 23-26 weeks compared with the young mice of 6-9 weeks (p < 0.05). In contrast, ovarian apoptosis was greatly increased in the aged mice compared to the young mice. This result suggests that Id-1 may have an implicated role in ovarian aging by associating with VEGF.

• Journal of Gastric Cancer
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• v.2 no.4
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• pp.195-199
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• 2002

Purpose: Angiogenesis is essential for tumor growth and metastasis and depends on the production of angiogenic factors that are secreted by tumor cells. Vascular endothelial growth factor (VEGF) is the most significant angiogenic factor and a selective mitogen for endothelial cells. VEGF, also known as the vascular permeability factor, acts on endothelial cells to increase microvascular permeability and directly stimulate the growth of new blood vessels. Several studies have reported that the expression of VEGF is correlated with hematogenous recurrence via angiogenesis in gastric carcinomas. This research evaluated the relationship between the expression of VEGF and hepatic and peritoneal recurrence in gastric carcinomas. Materials and Methods: Thirty specimens resected from patients with primary gastric carcinomas who had undergone curative resections were divided into three group: Group I, early gastric carcinomas without recurrence; Group II, advanced gastric carcinomas with hepatic recurrence; and Group III, advanced gastric carcinomas with peritoneal recurrence. The expression of VEGF and the density of the microvessel count were examined using immunohistochemistry. Results: 1) The expression of VEGF in Group II and Group III ($63.2\pm\24.3\%$) was stronger than that in Group I ($7\pm\4.2\%$). The expression of VEGF in Group II ($76.5\pm\13.2\%$) was stronger than that of the Group III ($50\pm\14.2\%$) (P<0.05). 2) The microvessel count in Group II ($49.9\pm14.5$) was more than that in Group I ($8.6\pm2.6$) and Group III ($29.1\pm18.1$) (P<0.05). 3) The microvessel count was increased significantly with increasing the expression of VEGF. Conclusions: The expression of VEGF is associated with advanced stomach cancer and hepatic recurrence has a higher expression of VEGF than peritoneal recurrence with neovascularization. Thus the expression of VEGF can be considered to be a useful indicator of recurrence in gastric carcinoma and especially in hepatic recurrence.

• Journal of Life Science
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• v.19 no.12
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• pp.1777-1786
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• 2009

Thymosin ${\beta}4$, a small protein containing 43 amino acids, has multi-functional roles in cell physiology. It was first identified as a thymic maturation factor and recently has been shown to accelerate wound healing, hair growth, angiogenesis, tumor growth, and metastasis. It was also reported to play a key role in developing organs, including the nervous system and heart. Thymosin ${\beta}4$ induces the expression of vascular endothelial cell growth factor (VEGF), laminin-5, and other important biologically active genes. Using tissue microarray analysis, we investigated the expression patterns of thymosin ${\beta}4$ and VEGF in various normal human adult tissues. Thymosin ${\beta}4$ was highly expressed in the liver, pancreas, ductal epithelium of the salivary gland, and heart, and moderately expressed in the skin, lung, spleen, lymph node, thymus, ureter, and blood endothelial cells in both the lung and adrenal gland. The expression of VEGF generally co-localized with thymosin ${\beta}4$ and VEGF was highly expressed in the pancreas, ureter, mammary gland, liver, esophagus, and blood endothelial cells in both the lung and adrenal gland. These results suggest that thymosin ${\beta}4$ plays an important role in the function of various organs and since the expression pattern of thymosin ${\beta}4$ co-localized with VEGF, part of that function may be to induce or maintain angiogenesis.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.39
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• pp.8.1-8.8
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• 2017

Background: For an effective bone graft for reconstruction of the maxillofacial region, an adequate vascular network will be required to supply blood, osteoprogenitor cells, and growth factors. We previously reported that the secretomes of bone marrow-derived mesenchymal stem cells (MSC-CM) contain numerous growth factors such as insulin-like growth factor (IGF)-1, transforming growth factor $(TGF)-{\beta}1$, and vascular endothelial growth factor (VEGF), which can affect the cellular characteristics and behavior of regenerating bone cells. We hypothesized that angiogenesis is an important step for bone regeneration, and VEGF is one of the crucial factors in MSC-CM that would enhance its osteogenic potential. In the present study, we focused on VEGF in MSC-CM and evaluated the angiogenic and osteogenic potentials of MSC-CM for bone regeneration. Methods: Cytokines in MSC-CM were measured by enzyme-linked immunosorbent assay (ELISA). Human umbilical vein endothelial cells (HUVECs) were cultured with MSC-CM or MSC-CM with anti-VEGF antibody (MSC-CM + anti-VEGF) for neutralization, and tube formation was evaluated. For the evaluation of bone and blood vessel formation with micro-computed tomography (micro-CT) and for the histological and immunohistochemical analyses, a rat calvarial bone defect model was used. Results: The concentrations of IGF-1, VEGF, and $TGF-{\beta}1$ in MSC-CM were $1515.6{\pm}211.8pg/mL$, $465.8{\pm}108.8pg/mL$, and $339.8{\pm}14.4pg/mL$, respectively. Tube formation of HUVECs, bone formation, and blood vessel formation were increased in the MSC-CM group but decreased in the MSC-CM + anti-VEGF group. Histological findings suggested that new bone formation in the entire defect was observed in the MSC-CM group although it was decreased in the MSC-CM + anti-VEGF group. Immunohistochemistry indicated that angiogenesis and migration of endogenous stem cells were much more abundant in the MSC-CM group than in the MSC-CM + anti-VEGF group. Conclusions: VEGF is considered a crucial factor in MSC-CM, and MSC-CM is proposed to be an adequate therapeutic agent for bone regeneration with angiogenesis.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.6
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• pp.2823-2828
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• 2012

Objective: To explore a new model of in-situ xenograft lymphangiogenesis of human colonic adenocarcinomas in nude mice. Method: On the basis of establishing subcutaneous xenograft lymphangiogenesis model of human colonic adenocarcinoms, in-situ xenografts were established through the in situ growth of the HT-29 human colonic adenocarcinoma cell line in nude mice. The numbers of lymphangiogenic microvessels, the expression of lymphatic endothelial cell markers lymphatic vessel endothelial hyaloronic acid receptor-1 (LYVE-1), D2-40 and the lymphatic endothelial growth factors vascular endothelial growth factor-C (VEGF-C), -D (VEGF-D) and receptor-3 (VEGFR-3) were compared by immunohistochemical staining, Western bolt and quantitative RT-PCR in xenograft in-situ models. Results: Some microlymphatics with thin walls, large and irregular or collapsed cavities and increased LMVD, with strong positive of LYVE-1, D2-40 in immunohistochemistry, were observed, identical with the morphological characteristics of lymphatic vessels and capillaries. Expression of LYVE-1 and D2-40 proteins and mRNAs were significantly higher in xenograpfts in-situ than in the negative control group(both P<0.01). Moreover, the expression of VEGF-C, VEGF-D and VEGFR-3 proteins and mRNAs were significantly higher in xenografts in-situ (both P<0.01), in conformity with the signal regulation of the VEGF-C,-D/VEGFR-3 axis of tumor lymphangiogenesis. Conclusions: In-situ xenografts of a human colonic adenocarcinoma cell line demonstrate tumor lymphangiogenesis. This novel in-situ animal model should be useful for further studying mechanisms of lymph node metastasis, drug intervention and anti-metastasis therapy in colorectal cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.9
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• pp.5301-5310
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• 2013

The biological mechanisms of cancer and associations with behavior of tumours need to be studied to understand progression and determine appropriate treatments. Here we investigated expression of VEGF, MMP-9 and E-cadherin in laryngeal SCCs and their relations with clinical behavior. This prospective study was based on 38 surgical specimens from patients with primary laryngeal SCC and data recorded in their cards. Expression of the three factors in tumor tissue was examined using immunohistochemistry and correlations with clinical parameters of primary tumors, regional lymph node metastases, stage of disease, histopathologic differentiation, and vascular/cartilage invasion were investigated. Regarding the cases with positive MMP-9 expression, the difference between well and moderately/poorly differentiated tumors was statistically significant. However, differences between early stage (stage I and II) and late-stage (stage III and IV) tumours, and between positive and negative for pLN metastasis were not. No significant relationship between positive VEGF and tumor differentiation or stage was apparent, but E-cadherin levels significantly differed between well and moderately/poorly differentiated tumours and with the presence of pLN metastasis. E-cadherin staining did not vary between MMP-9 positive and negative cases. In conclusion, MMP-9 may be a negative predictor of differentiation in laryngeal SCC, while E-cadherin is a predictor of differentiation and nodal metastases. Even if the difference between VEGF expression and tumor stage was not statistically significant, it seems that there exists some relationship, which might be clarified with a greater number of cases.

• Parasites, Hosts and Diseases
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• v.57 no.2
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• pp.117-125
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• 2019

Malarial infection induces tissue hypoxia in the host through destruction of red blood cells. Tissue hypoxia in malarial infection may increase the activity of $HIF1{\alpha}$ through an intracellular oxygen-sensing pathway. Activation of $HIF1{\alpha}$ may also induce vascular endothelial growth factor (VEGF) to trigger angiogenesis. To investigate whether malarial infection actually generates hypoxia-induced angiogenesis, we analyzed severity of hypoxia, the expression of hypoxia-related angiogenic factors, and numbers of blood vessels in various tissues infected with Plasmodium berghei. Infection in mice was performed by intraperitoneal injection of $2{\times}10^6$ parasitized red blood cells. After infection, we studied parasitemia and survival. We analyzed hypoxia, numbers of blood vessels, and expression of hypoxia-related angiogenic factors including VEGF and $HIF1{\alpha}$. We used Western blot, immunofluorescence, and immunohistochemistry to analyze various tissues from Plasmodium berghei-infected mice. In malaria-infected mice, parasitemia was increased over the duration of infection and directly associated with mortality rate. Expression of VEGF and $HIF1{\alpha}$ increased with the parasitemia in various tissues. Additionally, numbers of blood vessels significantly increased in each tissue type of the malaria-infected group compared to the uninfected control group. These results suggest that malarial infection in mice activates hypoxiainduced angiogenesis by stimulation of $HIF1{\alpha}$ and VEGF in various tissues.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.40 no.5
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• pp.240-245
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• 2014

Angiokeratoma is a benign cutaneous lesion of the capillaries, presenting as dilated vessels in the upper part of the dermis. Although this disorder is classified into various types and has been occasionally reported in the skin of the scrotum or extremities, the involvement of the oral cavity mucosa has been rarely reported. The present study reports a case of angiokeratoma circumscriptum in the buccal mucosa. The expression of vascular endothelial growth factor (VEGF) and both of its receptors (VEGFR-1 and VEGFR-2) was demonstrated by immunohistochemistry in the endothelial cells lining the dilated vessels. The expression of VEGFR-2 was higher than that of VEGFR-1 in the endothelial cells in the lesion, indicating an increased rate of endothelial cell proliferation within the lesion. Interestingly, some of the endothelial cells co-expressed VEGF and its two receptors. These results suggest that endothelial cells in the pathologically dilated vessels possess VEGF autocrine growth activity involved in vasculogenesis and maintenance in angiokeratoma lesions. To our knowledge, this is the second report published on isolated oral angiokeratoma confined to the buccal mucosa and the first case report on angiokeratoma circumscriptum involving the buccal mucosa.

• Clinical and Experimental Pediatrics
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• v.48 no.8
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• pp.886-893
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• 2005

Purpose : Kawasaki disease is the most common cause of systemic vasculitis in children less than 5 years of age. Recent immunohistochemistry findings suggest that many vascular growth factors play a role in the formation of the coronary artery lesions. Active remodeling of the coronary artery lesions in Kawasaki disease continues in the form of intimal proliferation and neoangiogenesis for several years after the onset of the disease. Intravenous immunoglobulin(IVIG) and corticosteroid have been used in the treatment of Kawasaki disease but the exact mechanism is not clear. We have investigated that IVIG and corticosteroid inhibited vascular endothelial growth factor(VEGF)-induced tube formation of endothelial cells in vitro on Matrigel assay. Methods : Human umbilical vein endothelial cells(HUVECs) were cultured and seeded on Matrigel coated 24 well plates in medium with or without the following agents : VEGF, VEGF plus IVIG, VEGF plus VEGF antibody, VEGF plus methylprednisolone, VEGF, IVIG plus methylprednisolone for 18 hours. The total length of tube structures in each photograph was quantified. Results : IVIG significantly inhibited the proliferation of HUVECs. The inhibitory effect of IVIG was also reversible. In the meantime, VEGF induced the differentiation of HUVECs into capillary like structures on Matrigel, which was inhibited by VEGF antibody in a dose-dependent manner. Interestingly, IVIG and methylprednisolone inhibited VEGF-induced tube formation of HUVECs. IVIG was more effective in inhibition than methylprednisolone alone. Conclusion : We revealed that VEGF induced the differentiation of HUVECs and this effect was inhibited by IVIG and methylprednisolone.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.12
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• pp.5049-5053
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• 2014

Background: To investigate the expression of CD44v3 and vascular endothelial growth factor-C (VEGF-C) and their relationship with lymph node metastasis in squamous cell carcinomas (SCC) of the uterine cervix. Materials and Methods: Expression of CD44v3 and VEGF-C was analyzed in 109 cases of cervical SCC by immunohistochemistry (IHC). The relationship was analyzed between expression and the patient age, histological differentiation, formation of tumor emboli in lymphoid vessels, lymph node metastasis, FIGO staging, and TNM classification. Results: Expression rates for both CD44v3 and VEGF-C were 43.1% in cervical SCC. The cells with positive immunohistochemical staining of CD44v3 were distributed mainly around the keratin pearls in well differentiated carcinomas, but distributed diffusely in the moderately and poorly differentiated lesions. VEGF-C was found stained positively in most of the tumor cells. There were differences in expression between normal epithelium and atypical hyperplasia as well as carcinoma. Both CD44v3 and VEGF-C were found to be associated positively with lymph node metastasis and TNM classification (both p=0.000). Neither CD44v3 nor VEGF-C was found to be associated with patient age, histological differentiation, formation of tumor emboli in lymphoid vessels and FIGO staging. CD44v3 was found to be associated with VEGF-C positively (p=0.000). Conclusions: Abnormal expression of CD44v3 and VEGF-C is associated closely with the lymph node metastasis in cervical SCC, and these agents may cooperate in carcinogenesis and development of metastatic lesions.