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Submitted on November 5, 2004
Accepted on March 29, 2005
Research fellow, Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina; Established investigator, Instituto de Biología y Medicina Experimental. CONICET, Argentina; Established investigator, Instituto de Investigaciones en Ingeniería Genética y Biología Molecular. CONICET and University of Buenos Aires, Argentina; Scientist, The Vollum Institute, Oregon Health & Science University, Portland, OR, USA
* To whom correspondence should be addressed. E-mail: dbecu{at}dna.uba.ar.
VEGF-A is an important angiogenic cytokine in cancer and pathological angiogenesis, and has been related to the antiangiogenic activity of dopamine in endothelial cells. We investigated VEGF expression, localization and function in pituitary hyperplasia of D2R- knockout female mice. Pituitaries from knockout mice showed increased protein and mRNA VEGF-A expression when compared with wild-type mice. In wild-type mice, prolonged treatment with the D2R antagonist, haloperidol, enhanced pituitary VEGF expression and prolactin release, suggesting that dopamine inhibits pituitary VEGF expression. VEGF expression was also increased in pituitary cells from knockout mice, even though these cells proliferated less in vitro when compared with wild-type cells, as determined by MTS proliferation assay, PCNA expression, and [3H]-thymidine incorporation. In contrast to other animal models, estrogen did not increase pituitary VEGF protein and mRNA expression, and lowered serum prolactin secretion in vivo and in vitro in both genotypes. VEGF (10 and 30 ng/ml) did not modify pituitary cell proliferation in either genotype, and increased prolactin secretion in vitro in estrogen-pretreated cells of both genotypes. But conditioned media from D2R- cells enhanced human umbilical vein cell (HUVEC) proliferation, and this effect could be partially inhibited by an antiVEGF antiserum. Finally, using dual labeling immunofluorescence and confocal laser microscopy we found that in the hyperplastic pituitaries VEGF-A was mostly present in follicle-stellate cells.
In conclusion, pituitary VEGF expression is under dopaminergic control, and even though VEGF does not promote pituitary cellular proliferation in vitro, it may be critical for pituitary angiogenesis through paracrine actions in the D2R knockout female mice.
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