• The Journal of Korean Physical Therapy
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• v.14 no.1
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• pp.219-226
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• 2002

Vascular endothelial growth factors(VEGFs) constitute a group of structurally and functionally related growth factor that modulate many important physiological functions of endothelial cells, especially angiogenesis. This paper explain substance, which participate in signaling transduction of VEGF, including Bcl-2, caspase, focal adhesion kinase(FAK), integrin ${\alpha}v{\beta}3$, MAP kinase, nitric oxide(NO)and prostacyclin(PGI2). Physical therapy enhance angiogenesis for repairment of injury which as wound healing, muscle contusion, cerebrovascular disease, rheumatoid arthritis. Therefore this review assist understanding for mechanism of physical therapy as therapeutic angiogenesis.

• Journal of Korean Neurosurgical Society
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• v.29 no.10
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• pp.1303-1308
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• 2000

Objectives : It has been known that vascular endothelial growth factor(VEGF), as an endothelial cell-specific mitogen, induces angiogenesis, and possesses vascular permeability and procoagulant properties. Peritumoral brain edema(PTBE) is a common accompaniment of malignant gliomas. It results from microvascular extravasation of plasma and proteins through the interendothelial spaces. The correlation between pathological grading, PTBE, neovascularization, and the expression of VEGF were analyzed in 31 patients with astrocytic tumors. Methods : Astrocytic tumor samples(8 astrocytomas, 14 anaplastic astrocytomas, and 9 glioblastomas) from 31 patients( 21 males and 10 females : average age $37{\pm}24$ years) who underwent surgery were examined retrospectively for the expression of VEGF and CD31(microvasculature) immunohistochemically. The extent of PTBE was examined by using preoperative CT or MRI as an edema index(EI). In addition to VEGF and CD31, several causative factors including tumor size, histologic type were compared with EI. Results : Only one of 8 astrocytomas, and majority of high grade(21 of 23 anaplastic astrocytomas and glioblastomas) tumors demonstrated PTBE(p<0.05). The majority of high grade tumors showed higher expression of VEGF (p<0.01). High grade tumors showed even higher CD31 expression(p<0.05), however, there was no close correlation between expression of VEGF and CD31. The EI was increased significantly, just as VEGF(p<0.01), but CD31 expression was not correlated with high EI. Conclusion : These data suggest that VEGF expression is closely correlated with PTBE and histological grading in astrocytic tumors. Microvasculature(CD31) in tumors is highly correlated with histological grading, however, shows no correlation with the expression of VEGF and PTBE.

• Biomolecules & Therapeutics
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• v.27 no.5
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• pp.474-483
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• 2019

Vascular endothelial growth factor (VEGF) plays a pivotal role in pathologic ocular neovascularization and vascular leakage via activation of VEGF receptor 2 (VEGFR2). This study was undertaken to evaluate the therapeutic mechanisms and effects of the tetrapeptide Arg-Leu-Tyr-Glu (RLYE), a VEGFR2 inhibitor, in the development of vascular permeability and choroidal neovascularization (CNV). In cultured human retinal microvascular endothelial cells (HRMECs), treatment with RLYE blocked VEGF-A-induced phosphorylation of VEGFR2, Akt, ERK, and endothelial nitric oxide synthase (eNOS), leading to suppression of VEGF-A-mediated hyper-production of NO. Treatment with RLYE also inhibited VEGF-A-stimulated angiogenic processes (migration, proliferation, and tube formation) and the hyperpermeability of HRMECs, in addition to attenuating VEGF-A-induced angiogenesis and vascular permeability in mice. The anti-vascular permeability activity of RLYE was correlated with enhanced stability and positioning of the junction proteins VE-cadherin, ${\beta}$-catenin, claudin-5, and ZO-1, critical components of the cortical actin ring structure and retinal endothelial barrier, at the boundary between HRMECs stimulated with VEGF-A. Furthermore, intravitreally injected RLYE bound to retinal microvascular endothelium and inhibited laser-induced CNV in mice. These findings suggest that RLYE has potential as a therapeutic drug for the treatment of CNV by preventing VEGFR2-mediated vascular leakage and angiogenesis.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.2
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• pp.499-503
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• 2012

The present study was based on the unexpected discovery that norcantharidin exerted anti-angiogenesis activity when effects on growth of human colon cancer were studied. The aim was to further verify this finding and explore possible mechanisms using a tumor xenograft model in nude mice. We confirmed that norcantharidin (5 or 15 mg/kg) could inhibit angiogenesis of human colon cancer in vivo. In vitro, crossing river assay, cell adhesion assay and tube formation assay indicated that NCTD could reduce the migration, adhesion and vascular network tube formation ability of HUVECs. At the same time, the expression levels of VEGF and VEGFR-2 proteins which play important roles in angiogenesis were reduced as examined by western blotting analysis. Taken together, the results firstly showed NCTD could inhibit angiogenesis of human colon cancer in vivo, probably associated with effects on migration, adhesion and vascular network tube formation of HUVECs and expression levels of VEGF and VEGFR-2 proteins.

• Natural Product Sciences
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• v.13 no.2
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• pp.128-131
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• 2007

Tumor angiogenesis is a critical step f3r the growth and metastasis of solid tumors. Vascular endothelial growth factor (VEGF) is the most important angiogenic molecule associated with tumor-induced neovascularization. VEGF exerts its activity through binding to its receptor tyrosine kinase, KDR/Flk-1, expressed on the surface of endothelial cells. This study was carried out to investigate inhibitory effect of extracts from root cortex of Paeonia suffruticosa Andrews on VEGF binding to VEGF receptor. The MeOH extract from P. suffrutiocosa Andr. inhibited the binding of KDR/Flk-1-Fc to immobilized VEGF$_{165}$ more than 45% at the concentration of 100 ${\mu}$g/mL. The MeOH extract was further fractionated into n-hexane, ethyl acetate, n-BuOH, and aqueous fractions. Among the four fractions, the ethyl acetate fraction from the root cortex of P. suffruticosa Andr. exhibited highly effective inhibition (${\approx}$ 79% inhibition) and then n-BuOH fraction (${\approx}$ 45% inhibition) on the binding of KDR/Flk-1-Fc to immobilized VEGF$_{165}$ at the concentration of 100 ${\mu}$g/mL. The ethyl acetate fraction from the root cortex of P. suffruticosa Andr. more efficiently blocked VEGF-induced human umbilical vein endothelial cell proliferation, than the growth of HT1080 human fibrosarcoma. Our results suggest that P. suffruticosa Andr. may be used as a candidate fur developing anti-angiogenic agent.

• Journal of Life Science
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• v.21 no.3
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• pp.417-423
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• 2011

Thymosin ${\beta}4$ (TB-4) has been reported to play a key role in tumor growth, metastasis and angiogenesis. In addition, TB-4 induced the expression of vascular endothelial growth factor (VEGF) and stabilized the hypoxia-inducible factor (HIF)-$1{\alpha}$ in melanoma cells. Although the importance of thymosin ${\beta}4$ in angiogenesis and metastasis has been proven, there are few studies that show the expression patterns of TB-4, VEGF and HIF-$1{\alpha}$. This study was conducted to analyze the relationship among these proteins in various tumors. Using tissue microarray analysis, we investigated the expression patterns of TB-4, VEGF and HIF-$1{\alpha}$ in various tumors to identify the expression patterns and relationships of these proteins in certain tumors. TB-4 was highly expressed in osteosarcoma, colon adenocarcinoma, esophageal squamous cell carcinoma, kidney and urinary bladder transitional carcinoma, lung cancer, and liver cancer. HIF-$1{\alpha}$ was highly expressed in nasal cavity inverted papilloma, lung cancer, and esophageal squamous cell carcinoma. The expression patterns of TB-4 and HIF-$1{\alpha}$ were almost similar and co-localized. VEGF expression was high in the blood vessels in tumors, but usually not high in the tumors themselves. VEGF was moderately expressed in stomach cancer, liver angiosarcoma, gall bladder adenocarcinoma, and uterus endometrial adenocarcinoma. The expression patterns of VEGF shows similarities in certain tumors including stomach cancer, osteosarcoma, liposarcoma, lung cancer, liver cancer, gall bladder adenocarcinoma, esophageal squamous cell carcinoma, stomach cancer, colorectal carcinoma and renal cell carcinoma. These results suggest that the expression patterns of TB-4, HIF-$1{\alpha}$ and VEGF were co-localized and related to tumorigenesis and angiogenesis of certain tumors.

• 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.

• Bulletin of the Korean Chemical Society
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• v.27 no.9
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• pp.1456-1458
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• 2006

• Journal of Korean Neurosurgical Society
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• v.29 no.12
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• pp.1584-1591
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• 2000

Objective : Until now, it has been little known about the biological mechanisms associated with the genesis, growth, and rupture of intracranial aneurysm. This study was performed to investigate and understand a part of these mechanisms. Materials and Methods : Immunohistochemical stains for angiogenesis growth factors(basic fibroblast growth factor (bFGF) and vascular endothelial growth factor(VEGF)) and selected vascular wall matrix proteins(alpha smooth muscle actin(${\alpha}SMA$) and collagen Type IV) were performed in fixed sections from a normal circle of Willis artery which was taken from the autopsy specimen as a control vessel and 17 aneurysmal wall specimens which was taken during surgical clipping of aneurysms. The staining intensity and distribution of immunoreactivity to angiogenesis growth factors and selected wall matrix proteins in control vessel and aneurysmal wall were examined and compared with each other. The difference of staining intensity according to the size of aneurysm was also investigated. Results : There was no immunoreactivity to bFGF and VEGF in the control vessel. bFGF immunoreactivity was exhibited in 15 of 17 aneurysm specimens around smooth muscle cells within the media of aneurysm. VEGF immunoreactivity was also exhibited in all aneurysm specimens in patches or diffusely affecting all layers of the aneurysmal wall. The degrees of intensity of bFGF and VEGF immunoexpression were proportionate roughly to the size of aneurysm. Strong immunoexpression of both factors were noticed in large aneurysm. A regularly arranged and defined band of immunoreactivity of ${\alpha}SMA$ was noticed in the media of the control vessel, whereas diffuse, faint, irregularly arranged ${\alpha}SMA$ was noticed in the aneurysmal wall. A regularly defined band of collagen Type IV immunoreactivity was also noticed in the subendothelium of the control vessel, whereas diffuse disorganized immunoreactivity of collagen Type IV was noticed in the entire wall of the aneurysm. Conclusion : These results indicate substantial evidences of abnormal expression of angiogenesis factors and changes of selected vascular wall matrix proteins in the wall of intracranial aneurysm. The unbalanced changes of angiogenesis factors and vascular wall matrix proteins in the wall of aneurysm may be one of the biological mechanisms for the growth and rupture of aneurysm.

• Oncology Letters
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• v.18 no.6
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• pp.6361-6370
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• 2019

Angiogenesis is an essential step in cancer progression and metastasis. Changes in the microRNA (miRNA or miR) expression profiles of endothelial cells (ECs) elicited by cancer cells promote angiogenesis. Vascular endothelial growth factor (VEGF), a key pro-angiogenic factor, influences miRNA expression in ECs; however, the exact role that VEGF serves in miRNA regulation during angiogenesis is poorly defined. The present study aimed to demonstrate the differential angiogenic effects on human umbilical vein endothelial cells (HUVECs) of five different colorectal cancer (CRC) cell lines by in vitro HUVEC migration and angiogenesis assays in response to CRC-conditioned medium (CM). Among the tested CMs, LoVo was the most effective cell line in eliciting HUVEC angiogenic phenotypes, at least partially due to its high VEGF level. It was also observed that pro-angiogenesis-regulatory miRNAs (angio-miRNA) miR-296, miR-132, miR-105 and miR-200 were upregulated in the VEGF-rich LoVo CM compared with the VEGF-scarce SW620 CM. In addition, treatment with VEGF receptor 2 inhibitor downregulated the pro-angio-miRNAs, with the exception of miR-132, suggesting that VEGF, as well as additional signaling, is required for angio-miRNA expression. Quantitative analyses on pro-angio-miRNA target expression suggested that independent pathways may be involved in the regulation of their expression. Overall, the data from the present study indicated that multiple paracrine factors, including VEGF secreted by CRCs, effectively modulated angio-miRNA expression, thus impacting their target expression and the angiogenic phenotypes of HUVECs.