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Transforming Growth Factor-ß Stimulates Vascular Endothelial Growth Factor Production by Folliculostellate Pituitary Cells

Max-Planck-Institute of Psychiatry (U.R., P.L., L.S., M.F., K.S., C.O., G.K.S.), Department of Endocrinology, Munich D-80804, Germany; and Laboratorio de Fisiologia y Biologia Molecular (E.A.), Department de Biologia, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428EHA, Argentina

Address all correspondence and requests for reprints to: Ulrich Renner, Ph.D., Max Planck Institute of Psychiatry, Department of Endocrinology, Kraepelinstrasse 10, D-80804 Munich, Germany. E-mail: renner{at}mpipsykl.mpg.de.

TGF-ß isoforms are expressed in the anterior pituitary and modulate the growth and function of endocrine pituitary cells. Recently, TGF-ß has been shown to stimulate growth and basic fibroblast growth factor secretion in nonendocrine folliculostellate (FS) pituitary cells. We therefore studied whether the production of FS cell-derived vascular endothelial growth factor (VEGF), the most important regulator of vascular permeability and angiogenesis, is affected by TGF-ß. We observed by RT-PCR that TtT/GF cells, which are FS mouse pituitary tumor cells, synthesize TGF-ß1, -ß2, and -ß3. They also express TGF-ß receptors types 1 and 2, as well as Smad2, Smad3, and Smad4 proteins, which are essential for TGF-ßbinding and signaling. Stimulation of TtT/GF cells with either TGF-ß1 or TGF-ß3 induced a rapid translocation of Smad2 into the cell nuclei. Both TGF-ß isoforms dose dependently stimulated VEGF production in TtT/GF cells, but not in lactosomatotroph GH3 cells. Time-course studies and suppression of TGF-ß-induced VEGF production by cycloheximide suggest that TGF-ß induces de novo synthesis of VEGF in folliculostellate cells, which is completely blocked by dexamethasone. In primary rat pituitary cell cultures, TGF-ß1 and -ß3 stimulated VEGF production. TGF-ß stimulation of VEGF production by folliculostellate cells could modulate intrapituitary vascular permeability and integrity as well as angiogenesis in an auto-/paracrine manner.