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Stimulatory Effect of Vascular Endothelial Growth Factor on Proliferation and Migration of Porcine Trophectoderm Cells and Their Regulation by the Phosphatidylinositol-3-Kinase-AKT and Mitogen-Activated Protein Kinase Cell Signaling Pathways1

ABSTRACT Vascular endothelial growth factor (VEGF), a potent stimulator for angiogenesis, is likely to regulate implantation by stimulating endometrial angiogenesis and vascular permeability. In addition to known angiogenetic effects, VEGF has been suggested to participate in development of the early embryo as a mediator of fetal-maternal dialogue. Current studies have determined VEGF in terms of its role in endometrial vascular events, but VEGF-induced effects on the peri-implantation conceptus (embryo and extraembryonic membranes) remains unknown. In the present study, endometrial VEGF, VEGF receptor-1 (VEGFR-1), and VEGF receptor-2 (VEGFR-2) mRNAs increased significantly during the peri-implantation period of pregnancy as compared to the estrous cycle. Expression of VEGF, VEGFR-1, and VEGFR-2 mRNAs was abundant in endometrial luminal and glandular epithelia, endothelial blood vessels, and scattered cells in the stroma and conceptus trophectoderm. In addition, porcine trophectoderm (pTr) cells treated with VEGF exhibited increased abundance of phosphorylated (p)-AKT1, p-ERK1/2, p-p70RSK, p-RPS6, and p-4EBP1 in a time-dependent manner. The addition of U0126, an inhibitor of ERK1/2, inhibited VEGF-induced ERK1/2 phosphorylation, but AKT1 phosphorylation was not affected. The addition of LY294002, a PI3K inhibitor, decreased VEGF-induced phosphorylation of ERK1/2 and AKT1. Furthermore, VEGF significantly stimulated proliferation and migration of pTr cells, but these effects were blocked by SB203580, U0126, rapamycin, and LY294002, which inhibit p38 MAPK, ERK1/2, mTOR, and PI3K, respectively. These results suggest that VEGF is critical to successful growth and development of pTr during early pregnancy and that VEGF-induced stimulatory effect is coordinately regulated by multiple cell signaling pathways, including PI3K-AKT1 and MAPK signaling pathways.