• Asian-Australasian Journal of Animal Sciences
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• v.22 no.6
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• pp.788-795
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• 2009

Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis under various physiological and pathological conditions. We found that the VEGF isoforms VEGF120, VEGF164, and VEGF188 were expressed in the bovine mammary gland and bovine mammary epithelial cells (bMECs). Expression of VEGF in the mammary gland was significantly higher during the lactation period than during the dry period. Although dexamethasone or prolactin alone had little effect on the expression of VEGF, that in dexamethasone-treated cells was significantly induced after additional treatment with prolactin. Furthermore, the VEGF expression induced by the combination of dexamethasone and prolactin was reduced by PD98059 in a dose-dependent manner. This combination also stimulated the phosphorylation of p44/p42 MAP kinase in these cells. These results strongly suggest that the combination of dexamethasone and prolactin stimulates VEGF expression in bMECs via p44/p42 MAP kinase.

• The Journal of Korean Society for Radiation Therapy
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• v.14 no.1
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• pp.165-174
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• 2002

Vascular endothelial growth factor (VEGF) has been identified as a peptide growth factor specific for vascular endothelial cells. In this study, we examined the effect of VEGF on radiation induced apoptosis and receptor/second messenger signal transduction pathway for VEGF effect in human umbilical vein endothelial cells (HUVECs). VEGF was found to protect HUVECs against the lethal effects of ionizing radiation by inhibiting the apoptosis induced in these cells by radiation exposure. VEGF (1-30 ng/ml) dose dependently inhibited apoptosis by irradiation. Pre-treatment with Flt-1 and Flk-l/KDR receptor blocked the VEGF-in duced antiapoptotic effect. Phosphatidylinositol 3'-kinase (PI3-kinase) specific inhibitor, Wortman in and LY294002, blocked the VEGF-induced antiapoptotic effect. These data suggest that VEGF may play an important role in survival of HUVECs due to the prevention of apoptotic cell death caused by some stresses such as ionizing radiation.

• BMB Reports
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• v.39 no.5
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• pp.469-478
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• 2006

Vascular endothelial growth factor (VEGF)-A, a major regulator for angiogenesis, binds and activates two tyrosine kinase receptors, VEGFR1 (Flt-1) and VEGFR2 (KDR/Flk-1). These receptors regulate physiological as well as pathological angiogenesis. VEGFR2 has strong tyrosine kinase activity, and transduces the major signals for angiogenesis. However, unlike other representative tyrosine kinase receptors which use the Ras pathway, VEGFR2 mostly uses the Phospholipase-$C{\gamma}$-Protein kinase-C pathway to activate MAP-kinase and DNA synthesis. VEGFR2 is a direct signal transducer for pathological angiogenesis including cancer and diabetic retinopathy, thus, VEGFR2 itself and the signaling appear to be critical targets for the suppression of these diseases. VEGFR1 plays dual role, a negative role in angiogenesis in the embryo most likely by trapping VEGF-A, and a positive role in adulthood in a tyrosine kinase-dependent manner. VEGFR1 is expressed not only in endothelial cells but also in macrophage-lineage cells, and promotes tumor growth, metastasis, and inflammation. Furthermore, a soluble form of VEGFR1 was found to be present at abnormally high levels in the serum of preeclampsia patients, and induces proteinurea and renal dysfunction. Therefore, VEGFR1 is also an important target in the treatment of human diseases. Recently, the VEGFR2-specific ligand VEGF-E (Orf-VEGF) was extensively characterized. Interestingly, the activation of VEGFR2 via VEGF-E in vivo results in a strong angiogenic response in mice with minor side effects such as inflammation compared with VEGF-A, suggesting VEGF-E to be a novel material for pro-angiogenic therapy.

• Molecules and Cells
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• v.28 no.1
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• pp.1-5
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• 2009

Vascular endothelial growth factor (VEGF) is essential for many angiogenic processes both in normal and pathological conditions. However, the signaling pathways involved in VEGF-induced angiogenesis are incompletely understood. The protein kinase D1 (PKD1), a newly described calcium/calmodulin-dependent serine/threonine kinase, has been implicated in cell migration, proliferation and membrane trafficking. Increasing evidence suggests critical roles for PKD1-mediated signaling pathways in endothelial cells, particularly in the regulation of VEGF-induced angiogenesis. Recent studies show that class IIa histone deacetylases (HDACs) are PKD1 substrates and VEGF signal-responsive repressors of myocyte enhancer factor-2 (MEF2) transcriptional activation in endothelial cells. This review provides a guide to PKD1 signaling pathways and the direct downstream targets of PKD1 in VEGF signaling, and suggests important functions of PKD1 in angiogenesis.

• Journal of Life Science
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• v.34 no.2
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• pp.128-137
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• 2024

This review discusses the pivotal role of vascular endothelial growth factors (VEGF) in angiogenesis and lymphangiogenesis, vital processes influencing vascular permeability, endothelial cell recruitment, and the maintenance of tumor-associated blood and lymphatic vessels. VEGF exerts its effects through tyrosine-kinase receptors, VEGFR-1, VEGFR-2, and VEGFR-3. This VEGF-VEGFR system is central not only to cancer but also to diseases arising from abnormal blood vessel and lymphatic vessel formation. In the context of cancer, VEGF and its receptors are essential for the development of tumor-associated vessels, making them attractive targets for therapeutic intervention. Various approaches, such as anti-VEGF antibodies, receptor antagonists, and VEGF receptor function inhibitors, are being explored to interfere with tumor growth. However, the clinical efficacy of anti-angiogenic agents remains uncertain and necessitates further refinement. The article also highlights the physiological role of VEGFs, emphasizing their involvement in endothelial cell functions, survival, and vascular permeability. The identification of five distinct VEGFs in humans (VEGF-A, VEGF-B, VEGF-C, VEGF-D, and PLGF) is discussed, along with the classification of VEGFRs as typical receptor tyrosine kinases with distinct signaling systems. The family includes VEGFR-1 and VEGFR-2, crucial in tumor biology and angiogenesis, and VEGFR-3, specifically involved in lymphangiogenesis. Overall, this review has provided a comprehensive overview of VEGF and VEGFR, detailing their roles in various diseases, including cancer. This is expected to further facilitate the utilization of VEGF and VEGFR as therapeutic targets.

• Biomolecules & Therapeutics
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• v.22 no.1
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• pp.1-9
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• 2014

Vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR) system has been shown to play central roles not only in physiological angiogenesis, but also in pathological angiogenesis in diseases such as cancer. Based on these findings, a variety of anti-angiogenic drugs, including anti-VEGF antibodies and VEGFR/multi-receptor kinase inhibitors have been developed and approved for the clinical use. While the clinical efficacy of these drugs has been clearly demonstrated in cancer patients, they have not been shown to be effective in curing cancer, suggesting that further improvement in their design is necessary. Abnormal expression of an endogenous VEGF-inhibitor sFlt-1 has been shown to be involved in a variety of diseases, such as preeclampsia and aged macular degeneration. In addition, various factors modulating angiogenic processes have been recently isolated. Given this complexity then, extensive studies on the interrelationship between VEGF signals and other angiogenesis-regulatory systems will be important for developing future strategies to suppress diseases with an angiogenic component.

• Microbiology and Biotechnology Letters
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• v.33 no.4
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• pp.308-314
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• 2005

Both high glucose and glucose degradation products (GDP) have been implicated in alterations of peritoneal membrane structure and function during long-term peritoneal dialysis (PD). The present study examined the role of GDP including methylglyoxal (MGO), acetaldehyde, and 3,4-dideoxyglucosone (3,4-DGE) in HPMC activation with respect to membrane hyperpermeability or fibrosis. The role of reactive oxygen species (ROS) and activation of protein kinase C (PKC) in GDP-induced HPMC activation were also examined. Using M199 culture medium as control, growth arrested and synchronized HPMC were continuously stimulated by MGO, acetaldehyde, and 3,4-DGE for 48 hours. Vascular endothelial growth factor (VEGF) was quantified as a marker of peritoneal membrane hyperpermeability and fibronectin and heat shock protein 47 (hsp47) as markers of fibrosis. Involvement of ROS and PKC was examined by the inhibitory effect of N-acetylcystein (NAC) or calphostin C, respectively. MGO significantly increased VEGF (1.9-fold), fibronectin (1.5-fold), and hsp47 (1.3-fold) secretion compared with control M199. NAC and calphostin C effectively inhibited MGO-induced VEGF upregulation. Acetaldehyde stimulated and 3,4-DGE inhibited VEGF secretion. Fibronectin secretion and hsp47 expression in HPMC were not affected by acetaldehyde or 3,4-DGE In conclusion, MGO upregulated VEGF and fibronectin secretion and hsp47 expression in HPMC, and PKC as well as ROS mediate MGO-induced VEGF secretion by HPMC. This implies that PKC activation and ROS generation by GDP may constitute important signals for activation of HPMC leading to progressive membrane hyperpermeability and accumulation of extracellular matrix and eventual peritoneal fibrosis.

• KSBB Journal
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• v.23 no.2
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• pp.142-146
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• 2008

In order to sprout and migrate, cells must secrete proteinases which are degrading the surrounding extracellular matrix. In this study, we examined the effect of mulberry extracts and combination of mulberry extracts and VEGF on human malignant glioma U-373-MG cells. Mulberry extracts induced the secretion of matrix metalloproteinase-9 (MMP-9) and suppressed the secretion of MMP-2 and plasmin. Mulberry extracts inhibited the VEGF-induced MMP-2, MMP-9 and plasmin secretion. It is therefore, suggested that mulberry extracts can suppress the VEGF-induced tumor angiogenesis in U-373-MG cells. Also, mulberry extracts induced the secretion of MMP-9 and plasmin through PI 3'-kinase pathway in U-373-MG cells.

• 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.

• 한국체육학회지인문사회과학편
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• v.51 no.3
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• pp.363-372
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• 2012

One of the major ocular complications of diabetes mellitus(DM) is retinopathy, which is characterized by increased neovascularization and neural degeneration in the retina. In the present study, we investigated the effects of treadmill exercise on retinopathy in the rats with DM. Thirty-two male Sprague-Dawley rats were divided into four groups(n = 8 in each group): control group, exercise group, DM-induction group, and DM-induction and exercise group. DM was induced by intraperitoneal injection of streptozotocin. The rats in the exercise groups were made to run on the treadmill for 30 min five times per a week, during 12 weeks. The expressions of phosphoinositide 3-kinase(PI3K), phospho-protein kinase B(pAkt), hypoxia inducible factor-1α(HIF-1α), and vascular endothelial growth factor(VEGF) in the retina were determined using western blot analysis and immunohistochemistry. In the present results, the expressions of PI3K, pAkt, HIF-1α, and VEGF in the retina of the diabetic rats were increased. Treadmill exercise suppressed HIF-1α and VEGF expressions through inhibition of PI3K/pAkt pathway in the diabetic rats. These results suggest that treadmill exercise may ameliorate the progression of diabetes-induced retinopathy by inhibiting neovascularization in the retina.