Involvement of ERK1/2 pathway in TGF‐β1‐induced VEGF secretion in normal human cytotrophoblast cells

Transforming growth factor-β1 (TGF-β1) plays a pivotal role in the angiogenesis during the development of placenta, but the intracellular signaling mechanism by which TGF-β1 stimulates this process remains poorly understood. In this article, we demonstrated that exposure of normal human cytotrophoblast cells to TGF-β1 stimulated the secretion of the VEGF gene encoding vascular endothelial growth factor, which is a key factor in angiogenesis. Meanwhile, treatment of normal human cytotrophoblast cells with TGF-β1-induced expression of HIF-1a, the regulated subunit of hypoxia-inducible factor 1, a known transactivator of the VEGF gene. Our data indicated that TGF-β1 induced extracellular signal- regulated kinase (ERK) 1/2 phosphorylation in normal human cytotrophoblast cells. Moreover, treating cells with PD98059, an inhibitor of ERK1/2 signaling, inhibited TGF-β1 stimulation of VEGF secretion and HIF-1a protein expression. These data indicated that in normal human cytotrophoblast cells, TGF-β1 induced HIF-1a-mediated VEGF secretion, and TGF-β1-stimulated-ERK1/2 activation may be involved in this process. Mol. Reprod. Dev. 68: 198–204, 2004. © 2004 Wiley-Liss, Inc.