Vascular Endothelial Growth Factor (VEGF), VEGF Receptors and Their Inhibitors for Antiangiogenic Tumor Therapy

The aim of this study was to investigate the expression of vascular endothelial growth factor (VEGF) receptors, the fms-like tyrosine kinase (flt-1) and kinase insert domain-containing region (KDR), in corpora lutea obtained at different stages of the oestrous cycle and during pregnancy in rats. Immunohistochemistry revealed that both flt-1 and KDR were localized in luteal cells in addition to vascular endothelial cells, and that the intensity of staining was stronger in pregnant rats than in cyclic rats. Rats undergoing hypophysectomy-hysterectomy on day 12 of pregnancy were treated with oestradiol until day 15 of pregnancy to determine whether oestradiol is involved in expression of flt-1 and KDR mRNA in the corpus luteum during mid-pregnancy. The flt-1 and KDR mRNA contents in the corpus luteum were decreased significantly by hypophysectomy-hysterectomy, and these decreases recovered significantly after oestradiol treatment. Changes in the mass of the corpus luteum and serum progesterone concentrations paralleled the changes in expression of flt-1 and KDR mRNA. Developmental studies indicated that flt-1 and KDR mRNA contents in the corpus luteum were constant until day 15 of pregnancy but decreased significantly on day 21 of pregnancy. In conclusion, both flt-1 and KDR were expressed in luteal cells in addition to vascular endothelial cells, and expression was upregulated by oestradiol during mid-pregnancy. flt-1 and KDR may play a role in development of the corpus luteum and in production of progesterone during mid-pregnancy in rats.

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Immunohistochemical detection of vascular endothelial growth factor (VEGF) and VEGF receptors Flt-1 and KDR/Flk-1 in the cochlea of guinea pigs

Hearing Research ◽

10.1016/s0378-5955(01)00262-3 ◽

2001 ◽

Vol 155 (1-2) ◽

pp. 175-180 ◽

Cited By ~ 16

Author(s):

Olaf Michel ◽

Alexander Hess ◽

Wilhelm Bloch ◽

Annette Schmidt ◽

Eberhard Stennert ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Guinea Pigs ◽

Vascular Endothelial ◽

Vegf Receptors ◽

Immunohistochemical Detection ◽

Endothelial Growth Factor

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Vascular Endothelial Growth Factor and Glioma Angiogenesis: Coordinate Induction of VEGF Receptors, Distribution of VEGF Protein and Possible In Vivo Regulatory Mechanisms

Retina ◽

10.1097/00006982-199515020-00023 ◽

1995 ◽

Vol 15 (2) ◽

pp. 175 ◽

Cited By ~ 1

Author(s):

K H Plate ◽

G Breier ◽

H A Weich ◽

H D Mennel ◽

W Risau

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Regulatory Mechanisms ◽

Vascular Endothelial ◽

Vegf Receptors ◽

Endothelial Growth Factor ◽

Vegf Protein

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Localization of vascular endothelial growth factor (VEGF) receptors in normal and adenomatous pituitaries: detection of a non-endothelial function of VEGF in pituitary tumours

Journal of Endocrinology ◽

10.1677/joe.1.06992 ◽

2006 ◽

Vol 191 (1) ◽

pp. 249-261 ◽

Cited By ~ 39

Author(s):

Chiara Onofri ◽

Marily Theodoropoulou ◽

Marco Losa ◽

Eberhard Uhl ◽

Manfred Lange ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Cell Proliferation ◽

Endothelial Cells ◽

Pituitary Adenoma ◽

Growth Factor ◽

Pituitary Adenomas ◽

Vascular Endothelial ◽

Vegf Receptors ◽

Pituitary Tumours ◽

Endothelial Growth Factor

As for any solid tumour, pituitary adenoma expansion is dependent on neovascularization through angiogenesis. In this process, vascular endothelial growth factor (VEGF) and its receptors VEGFR-1, VEGFR-2 and neuropilin-1 (NRP-1) may play an outstanding role. The intention of this work was to study the expression/localization and possible function of VEGF receptors in pituitary adenomas. VEGF receptor mRNA and protein expression was studied by in situ hybridization, immunohistochemistry and RT-PCR in 6 normal human pituitaries, 39 human pituitary adenomas and 4 rodent pituitary adenoma cell lines. VEGFR-1 expressing somatotroph MtT-S cells were used as a model to study the role of VEGF on cell proliferation and to elucidate the underlying mechanism of action. In normal pituitaries, VEGFR-1 was detected in endocrine cells, whereas VEGFR-2 and NRP-1 were exclusively expressed in endothelial cells. In pituitary tumours, a heterogeneous VEGFR expression pattern was observed by IHC. VEGFR-1, VEGFR-2 and NRP-1 were detected in 24, 18 and 17 adenomas respectively. In the adenomas, VEGFR-1 was expressed in epithelial tumour cells and VEGFR-2/NRP-1 in vessel endothelial cells. Functional studies in VEGFR-1-positive MtT-S cells showed that the ligands of VEGFR-1 significantly stimulated cell proliferation. This effect was mediated through the phosphatidylinositol-3-kinase-signalling pathway and involves induction of cyclin D1 and Bcl-2. Based on our results, we speculate that the ligands of VEGF receptors, such as VEGF-A and placenta growth factor, not only play a role in angiogenesis in pituitary adenomas, but also affect the growth of pituitary tumour cells through VEGFR-1.

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Vascular Endothelial Growth Factor Receptors in Human Mesangiumin Vitroand in Glomerular Disease

Journal of the American Society of Nephrology ◽

10.1681/asn.v1171236 ◽

2000 ◽

Vol 11 (7) ◽

pp. 1236-1243 ◽

Cited By ~ 3

Author(s):

STEPHEN THOMAS ◽

JOHANN VANUYSTEL ◽

GABRIELLA GRUDEN ◽

VERÓNICA RODRÍGUEZ ◽

DAVINA BURT ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Ex Vivo ◽

Fold Increase ◽

Vascular Endothelial ◽

Vegf Receptors ◽

Glomerular Diseases ◽

Neuropilin 1 ◽

Endothelial Growth Factor

Abstract. Mesangial cell proliferation and growth factor over-expression are characteristic features of several glomerular diseases. Vascular endothelial growth factor (VEGF), a potent mitogen, is expressed in podocytes in the glomerulus, and VEGF receptors (flt-1, KDR, and neuropilin-1) are present on endothelial cells and other cell types. This study examined whether human mesangial cells (HMC) express VEGF receptorsin vitroandex vivoand evaluated the effect of VEGF on HMC proliferation. All receptor types were detected in HMCin vitroby immunofluorescence and Western blotting. VEGF165induced a dose-responsive increase in3H-thymidine incorporation (25 ng/ml VEGF165: 2.3-fold increase ; 50 ng/ml : 3.8-fold ; 100 ng/ml : 4.8-fold ; 200 ng/ml : 3.4-fold ;P= 0.016) and in cell number (50 ng/ml VEGF165: 1.2-fold increase ; 100 ng/ml : 1.6-fold ; 200 ng/ml : 1.4-fold ;P= 0.005), effects prevented by an anti-VEGF165polyclonal neutralizing antibody (100 μg/ml). The proliferative effect was confirmed by a tetrazolium dye-based assay (100 ng/ml VEGF165: 1.4-fold increase). Inex vivoexperiments, VEGF receptors in biopsy material from normal and diseased kidneys were detected by immunohistochemistry. No mesangial flt-1 receptor staining was seen in normal renal cortical tissue samples, and only weak mesangial KDR staining was detected. In contrast, mesangial flt-1 and KDR receptor staining were both clearly seen in biopsy samples from proliferative renal diseases. In conclusion, flt-1, KDR, and neuropilin-1 are present on cultured HMC, and VEGF165induces HMC proliferation. In addition, the flt-1 and KDR receptors are expressed in the mesangium in mesangioproliferative disease.

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