Nuclear Translocation of Phosphorylated STAT3 Is Essential for Vascular Endothelial Growth Factor-induced Human Dermal Microvascular Endothelial Cell Migration and Tube Formation

• Published in: The Journal of biological chemistry 2003-10, Vol.278 (41), p.40026-40031
• Main Authors: Yahata, Yoko, Shirakata, Yuji, Tokumaru, Sho, Yamasaki, Kenshi, Sayama, Koji, Hanakawa, Yasushi, Detmar, Michael, Hashimoto, Koji
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus; Adenovirus; Cell Culture Techniques; Cell Division - drug effects; Cell Division - physiology; Cell Line; Cell Movement - drug effects; Cell Movement - physiology; Collagen; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - growth & development; Endothelium, Vascular - metabolism; Gels; Humans; Mutation; Phosphorylation; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Skin - blood supply; STAT3 Transcription Factor; Trans-Activators - chemistry; Trans-Activators - genetics; Trans-Activators - metabolism; Transfection; Vascular Endothelial Growth Factor A - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M301866200

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.