title: Elevated Slit2 Activity Impairs VEGF-Induced Angiogenesis and Tumor Neovascularization in EphA2-Deficient Endothelium.
abstract: Angiogenic remodeling during embryonic development and in adult tissue homeostasis is orchestrated by cooperative signaling between several distinct molecular pathways, which are often exploited by tumors. Indeed, tumors upregulate proangiogenic molecules while simultaneously suppressing angiostatic pathways to recruit blood vessels for growth, survival, and metastatic spread. Understanding how cancers exploit proangiogenic and antiangiogenic signals is a key step in developing new, molecularly targeted antiangiogenic therapies. While EphA2, a receptor tyrosine kinase (RTK), is required for VEGF-induced angiogenesis, the mechanism through which these pathways intersect remains unclear. Slit2 expression is elevated in EphA2-deficient endothelium, and here it is reported that inhibiting Slit activity rescues VEGF-induced angiogenesis in cell culture and in vivo, as well as VEGF-dependent tumor angiogenesis, in EphA2-deficient endothelial cells and animals. Moreover, blocking Slit activity or Slit2 expression in EphA2-deficient endothelial cells restores VEGF-induced activation of Src and Rac, both of which are required for VEGF-mediated angiogenesis. These data suggest that EphA2 suppression of Slit2 expression and Slit angiostatic activity enables VEGF-induced angiogenesis in vitro and in vivo, providing a plausible mechanism for impaired endothelial responses to VEGF in the absence of EphA2 function.
  
  
  CONCLUSIONS
  Modulation of angiostatic factor Slit2 by EphA2 receptor regulates endothelial responses to VEGF-mediated angiogenesis and tumor neovascularization.
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Victoria
authors.initials: V
authors.lastname: Youngblood
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Shan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Wenqiang
authors.initials: W
authors.lastname: Song
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Debra
authors.initials: D
authors.lastname: Walter
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Yoonha
authors.initials: Y
authors.lastname: Hwang
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee. Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee. Department of Cellular and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee. Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee. Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, Tennessee.
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee. Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee. dana.brantley@vanderbilt.edu.
authors.forename: Dana M
authors.initials: DM
authors.lastname: Brantley-Sieders
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D004727:Endothelium / Q000098:blood supply* / Q000378:metabolism; D005260:Female; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008168:Lung / Q000098:blood supply / Q000166:cytology; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D036104:Receptor, EphA2 / Q000172:deficiency*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D000098552:Slit Homolog 2 Protein
chemical_list: D017077:Culture Media, Conditioned; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D036104:Receptor, EphA2; D000098552:Slit Homolog 2 Protein