Expression and Distribution of Vascular Endothelial Growth Factor Receptor Flk-1 in the Rat Pituitary

Vidal, Sergio; Lloyd, Ricardo V.; Moya, Lucas; Scheithauer, Bernd W.; Kovács, Kálmán

doi:10.1177/002215540205000410

Cited by 30 publications

(26 citation statements)

References 34 publications

(57 reference statements)

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“…Vascular endothelial growth factor (VEGF) expression was also assessed as positive control. It is up-regulated by hypoxia through direct involvement of HIF-1␣ (43) and is also produced by hormoneproducing as well as capillary endothelial cells of the anterior pituitary gland (44,45). CoCl 2 decreased hGH RNA levels significantly (p Ͻ 0.001, n ϭ 6) and by a similar extent (ϳ60%) to that observed with insulin treatment (Fig.…”

Section: Induction Of Hif-1␣ Protein By Cocl 2 Treatment Mimics the Ementioning

confidence: 71%

Negative Regulation of Human Growth Hormone Gene Expression by Insulin Is Dependent on Hypoxia-inducible Factor Binding in Primary Non-tumor Pituitary Cells

Vakili¹,

Jin

Cattini

2012

Journal of Biological Chemistry

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Background: Insulin regulation of human growth hormone has not been studied in non-tumor pituitary cells. Results: Insulin decreases growth hormone RNA levels via an insulin-induced transcription factor and chromatin remodeling. Conclusion: The somatotroph and growth hormone gene expression are targets for insulin signaling. Significance: This may explain the early and rapid suppression of growth hormone levels seen in hyperinsulinemic individuals.

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Section: Induction Of Hif-1␣ Protein By Cocl 2 Treatment Mimics the Ementioning

confidence: 71%

Negative Regulation of Human Growth Hormone Gene Expression by Insulin Is Dependent on Hypoxia-inducible Factor Binding in Primary Non-tumor Pituitary Cells

Vakili¹,

Jin

Cattini

2012

Journal of Biological Chemistry

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“…It has been reported that VEGF and its receptor Flk-1 are expressed in GH3 cells (31,48), and, furthermore, it has been shown that VEGF induces Ca 2ϩ influx in epithelial cells. Here we show, for the first time, that VEGF receptor (VEGFR) activation stimulates depolarization-induced Ca 2ϩ influx in GH3 cells, suggesting a positive effect of VEGFR, an RTK, on VDCC activity.…”

Section: Discussionmentioning

confidence: 99%

Different kinases regulate activation of voltage-dependent calcium channels by depolarization in GH3 cells

Vela

Pérez-Millán²,

Becú-Villalobos³

et al. 2007

American Journal of Physiology-Cell Physiology

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The L-type Ca2+ channel is the primary voltage-dependent Ca2+-influx pathway in many excitable and secretory cells, and direct phosphorylation by different kinases is one of the mechanisms involved in the regulation of its activity. The aim of this study was to evaluate the participation of Ser/Thr kinases and tyrosine kinases (TKs) in depolarization-induced Ca2+ influx in the endocrine somatomammotrope cell line GH3. Intracellular Ca2+ concentration ([Ca2+]i) was measured using a spectrofluorometric method with fura 2-AM, and 12.5 mM KCl (K+) was used as a depolarization stimulus. K+ induced an abrupt spike (peak) in [Ca2+]i that was abolished in the presence of nifedipine, showing that K+ enhances [Ca2+]i, preferably activating L-type Ca2+ channels. H89, a selective PKA inhibitor, significantly reduced depolarization-induced Ca2+ mobilization in a concentration-related manner when it was applied before or after K+, and okadaic acid, an inhibitor of Ser/Thr phosphatases, which has been shown to regulate PKA-stimulated L-type Ca2+ channels, increased K+-induced Ca2+ entry. When PKC was activated by PMA, the K+-evoked peak in [Ca2+]i, as well as the plateau phase, was significantly reduced, and chelerythrine (a PKC inhibitor) potentiated the K+-induced increase in [Ca2+]i, indicating an inhibitory role of PKC in voltage-dependent Ca2+ channel (VDCC) activity. Genistein, a TK inhibitor, reduced the K+-evoked increase in [Ca2+]i, but, unexpectedly, the tyrosine phosphatase inhibitor orthovanadate reduced not only basal Ca2+ levels but, also, Ca2+ influx during the plateau phase. Both results suggest that different TKs may act differentially on VDCC activation. Activation of receptor TKs with epidermal growth factor (EGF) or vascular endothelial growth factor potentiated K+-induced Ca2+ influx, and AG-1478 (an EGF receptor inhibitor) decreased it. However, inhibition of the non-receptor TK pp60 c-Src enhanced K+-induced Ca2+ influx. The present study strongly demonstrates that a complex equilibrium among different kinases and phosphatases regulates VDCC activity in the pituitary cell line GH3: PKA and receptor TKs, such as vascular endothelial growth factor receptor and EGF receptor, enhance depolarization-induced Ca2+ influx, whereas PKC and c-Src have an inhibitory effect. These kinases modulate membrane depolarization and may therefore participate in the regulation of a plethora of intracellular processes, such as hormone secretion, gene expression, protein synthesis, and cell proliferation, in pituitary cells.

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“…The pituitary contains abundant VEGF as well as VEGFR2 (Ochoa et al, 2000;Vidal et al, 2002), and VEGF participates in the formation of the vascular network of a new pituitary tumor (Banerjee et al, 2000;Kim et al, 2005). It is also involved in the proliferative action of estrogen on lactotropes (Onofri et al, 2004), and increased tumoral VEGF expression was observed during estrogen-induced prolactinoma development in rats (Banerjee et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Inhibitory Effects of Antivascular Endothelial Growth Factor Strategies in Experimental Dopamine-Resistant Prolactinomas

Luque

Pérez-Millán²,

Ornstein³

et al. 2011

J Pharmacol Exp Ther

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Prolactin-secreting adenomas are the most frequent type among pituitary tumors, and pharmacological therapy with dopamine agonists remains the mainstay of treatment. But some adenomas are resistant, and a decrease in the number or function of dopamine D2 receptors (D2Rs) has been described in these cases. D2R knockout [Drd2(Ϫ/Ϫ)] mice have chronic hyperprolactinemia and pituitary hyperplasia and provide an experimental model for dopamine agonist-resistant prolactinomas. We described previously that disruption of D2Rs increases vascular endothelial growth factor (VEGF) expression. We therefore designed two strategies of antiangiogenesis using prolactinomas generated in Drd2(Ϫ/Ϫ) female mice: direct intra-adenoma mVEGF R1 (Flt-1)/Fc chimera (VEGF-TRAP) injection for 3 weeks [into subcutaneously transplanted pituitaries from Drd2(Ϫ/Ϫ) mice] and systemic VEGF neutralization with the specific monoclonal antibody G6-31. Both strategies resulted in substantial decrease of prolactin content and lactotrope area, and a reduction in tumor size was observed in in situ prolactinomas. There were significant decreases in vascularity, evaluated by cluster of differentiation molecule 31 vessel staining, and proliferation (proliferating cell nuclear antigen staining) in response to both anti-VEGF treatments. These data demonstrate that the antiangiogenic approach was effective in inhibiting the growth of in situ dopamine-resistant prolactinomas as well as in the transplanted adenomas. No differences in VEGF protein expression were observed after either anti-VEGF treatment, and, although serum VEGF was increased in G6-31-treated mice, pituitary activation of the VEGF receptor 2 signaling pathway was reduced. Our results indicate that, even though the role of angiogenesis in pituitary adenomas is contentious, VEGF might contribute to adequate vascular supply and represent a supplementary therapeutic target in dopamine agonist-resistant prolactinomas.

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Expression and Distribution of Vascular Endothelial Growth Factor Receptor Flk-1 in the Rat Pituitary

Cited by 30 publications

References 34 publications

Negative Regulation of Human Growth Hormone Gene Expression by Insulin Is Dependent on Hypoxia-inducible Factor Binding in Primary Non-tumor Pituitary Cells

Negative Regulation of Human Growth Hormone Gene Expression by Insulin Is Dependent on Hypoxia-inducible Factor Binding in Primary Non-tumor Pituitary Cells

Different kinases regulate activation of voltage-dependent calcium channels by depolarization in GH3 cells

Inhibitory Effects of Antivascular Endothelial Growth Factor Strategies in Experimental Dopamine-Resistant Prolactinomas

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