title: Slit2 suppresses endothelial cell proliferation and migration by inhibiting the VEGF-Notch signaling pathway.
abstract: Slit homolog 2 (Slit2) is distributed in various tissues and participates in numerous cellular processes; however, the role of Slit2 in the regulation of angiogenesis remains controversial, since it has previously been reported to exert proangiogenic and antiangiogenic activities. The present study aimed to investigate the effects of Slit2 on vascular endothelial cell proliferation and migration in vitro, and to reveal the possible underlying signaling pathway. Aortic endothelial cells were isolated from Sprague Dawley rats and cultured. Cell proliferation assay, cell migration assay, immunocytochemistry and small interfering RNA transfection were subsequently performed. The results demonstrated that exogenous Slit2 administration markedly suppressed TNF‑α‑induced endothelial cell proliferation and migration in vitro. In addition, TNF‑α application upregulated the protein expression levels of vascular endothelial growth factor (VEGF) and Notch in RAECs, whereas Slit2 administration downregulated VEGF and Notch expression in RAECs cultured in TNF‑α conditioned medium. Further studies indicated that knockdown of VEGF suppressed the effects of TNF‑α on the induction of RAEC proliferation and migration. VEGF knockdown‑induced inhibition of RAEC proliferation and migration in TNF‑α conditioned medium was also achieved without Slit2 administration. Furthermore, VEGF knockdown markedly decreased Notch1 and Notch2 expression. These results indicated that Slit2 suppresses TNF‑α‑induced vascular endothelial cell proliferation and migration in vitro by inhibiting the VEGF‑Notch signaling pathway. Therefore, Slit2 may inhibit the proliferation and migration of endothelial cells during vascular development.
authors.affiliation: Department of Vascular Surgery, The Fourth Affiliated Hospital, Kunming Medical University, Kunming, Yunnan 650021, P.R. China.
authors.forename: Guo-Jian
authors.initials: GJ
authors.lastname: Li
authors.affiliation: Department of Vascular Surgery, The Fourth Affiliated Hospital, Kunming Medical University, Kunming, Yunnan 650021, P.R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Vascular Surgery, The Fourth Affiliated Hospital, Kunming Medical University, Kunming, Yunnan 650021, P.R. China.
authors.forename: Guo-Kai
authors.initials: GK
authors.lastname: Yang
authors.affiliation: Department of Vascular Surgery, The Fourth Affiliated Hospital, Kunming Medical University, Kunming, Yunnan 650021, P.R. China.
authors.forename: Jia
authors.initials: J
authors.lastname: Wan
authors.affiliation: Department of Vascular Surgery, The Fourth Affiliated Hospital, Kunming Medical University, Kunming, Yunnan 650021, P.R. China.
authors.forename: Dao-Lei
authors.initials: DL
authors.lastname: Cui
authors.affiliation: Department of Vascular Surgery, The Fourth Affiliated Hospital, Kunming Medical University, Kunming, Yunnan 650021, P.R. China.
authors.forename: Zhen-Huan
authors.initials: ZH
authors.lastname: Ma
authors.affiliation: Department of Vascular Surgery, The Fourth Affiliated Hospital, Kunming Medical University, Kunming, Yunnan 650021, P.R. China.
authors.forename: Ling-Juan
authors.initials: LJ
authors.lastname: Du
authors.affiliation: Department of Cardiovascular Surgery, The First Affiliated Hospital, Kunming Medical University, Kunming, Yunnan 650032, P.R. China.
authors.forename: Gui-Min
authors.initials: GM
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D000098552:Slit Homolog 2 Protein
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D051880:Receptors, Notch; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D000098552:Slit Homolog 2 Protein