Transforming growth factor-β stimulates vascular endothelial growth factor production by folliculostellate pituitary cells

Abstract

TGF-β isoforms are expressed in the anterior pituitary and modulate the growth and function of endocrine pituitary cells. Recently, TGF-β 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-β. We observed by RT-PCR that TtT/GF cells, which are FS mouse pituitary tumor cells, synthesize TGF-β1, -β2, and -β3. They also express TGF-β receptors types 1 and 2, as well as Smad2, Smad3, and Smad4 proteins, which are essential for TGF-β binding and signaling. Stimulation of TtT/GF cells with either TGF-β1 or TGF-β3 induced a rapid translocation of Smad2 into the cell nuclei. Both TGF-β isoforms dose dependently stimulated VEGF production in TtT/GF cells, but not in lactosomatotroph GH3 cells. Time-course studies and suppression of TGF-β-induced VEGF production by cycloheximide suggest that TGF-β induces de novo synthesis of VEGF in folliculostellate cells, which is completely blocked by dexamethasone. In primary rat pituitary cell cultures, TGF-β and -β3 stimulated VEGF production. TGF-β stimulation of VEGF production by folliculostellate cells could modulate intrapituitary vascular permeability and integrity as well as angiogenesis in an auto-/paracrine manner.