Abstract
Vascular endothelial growth factor (VEGF) is a potent, multifunctional, endothelial-cell-specific growth factor. It stimulates proliferation and migration of endothelial cells. Characterization of intracellular signal transduction after VEGF and VEGF receptor (VEGFR) interaction has demonstrated the involvement of the mitogen-activated protein kinase pathway. However, several studies indicated that signal transducers and activators of transcription (STAT) is another important pathway downstream of VEGF/VEGFR interaction. Therefore, we studied the role of STAT3 in the migration and tube formation of the human dermal microvascular endothelial cells (HDMEC). HDMEC expressed phosphorylated forms of STAT1, STAT3, and STAT5, and a marked increase of phosphorylated STAT3 in the nuclear fraction after addition of VEGF was observed by Western blot and immunohistochemical staining. To verify the functional implication of STAT3 phosphorylation in HDMEC migration, we introduced a dominant-negative STAT3 using adenovirus vector system. Dominant-negative STAT3 abolished the VEGF-induced nuclear translocation of phosphorylated STAT3 and inhibited HDMEC migration completely. Dominant-negative STAT3 also suppressed VEGF-induced HDMEC tube formation on Matrigel and on collagen gel. These data demonstrate that STAT3 and its phosphorylation are involved in the downstream pathway of VEGF/VEGFR interaction and regulate VEGF-induced HDMEC migration and tube formation.
Highlights
Vascular endothelial growth factor (VEGF)1 is a member of the platelet-derived growth factor superfamily and an endothelial-cell-specific growth factor
Expression Profile of signal transducers and activators of transcription (STAT) in human dermal microvascular endothelial cells (HDMEC) and Translocation of Phosphorylated STAT3 into the Nucleus by VEGF—Because STAT protein expression differs depending on cell types, we investigated STAT protein expression in HDMEC
Because phosphorylated STAT proteins translocate into the nucleus, we examined the expression of phosphorylated STAT1, STAT3, and STAT5 in the nuclear fraction
Summary
Vascular endothelial growth factor (VEGF)1 is a member of the platelet-derived growth factor superfamily and an endothelial-cell-specific growth factor. We studied the role of STAT3 in the migration and tube formation of the human dermal microvascular endothelial cells (HDMEC). Dominant-negative STAT3 abolished the VEGF-induced nuclear translocation of phosphorylated STAT3 and inhibited HDMEC migration completely. Dominant-negative STAT3 suppressed VEGF-induced HDMEC tube formation on Matrigel and on collagen gel.
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