title: Angiopoietin-4 inhibits angiogenesis and reduces interstitial fluid pressure.
abstract: Angiopoietins (Ang) are involved in the remodeling, maturation, and stabilization of the vascular network. Ang-4 was discovered more recently; thus, its effect on angiogenesis and its interplay with other angiogenic factors have not been equivocally established. The role of Ang-4 in angiogenesis was tested in Matrigel chambers implanted into the subcutaneous space of nude mice. Ang-4 inhibited the angiogenic response of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and GLC19 tumor cells. In Matrigel chambers with Ang-4-transfected cells, the mean response was significantly lower than that of mock cells. Subcutaneous tumor interstitial fluid pressure (IFP) was significantly lower in Ang-4-transfected GLC19 tumors than in mock-transfected tumors. IFP reduction in Ang-4-transfected tumors was comparable to the reduction seen after bevacizumab treatment. In vitro, we examined the effect of recombinant Ang-4 on endothelial cell migration in Boyden chambers. Human umbilical vein endothelial cell (HUVEC) migration induced by bFGF and VEGF was inhibited by Ang-4 to control levels. In conclusion, we show that rhAng-4, as well as transfection with Ang-4, inhibits angiogenesis induced by GLC19 tumor cells and that Ang-4 expression reduces elevated tumor IFP. In addition, we demonstrate that rhAng-4 inhibits HUVEC migration and growth factor-induced angiogenesis.
authors.affiliation: Laboratory of Experimental Oncology, Institute of Molecular Pathology, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors.forename: Minna W B
authors.initials: MW
authors.lastname: Olsen
authors.forename: Carsten D
authors.initials: CD
authors.lastname: Ley
authors.forename: Nanna
authors.initials: N
authors.lastname: Junker
authors.forename: Anker J
authors.initials: AJ
authors.lastname: Hansen
authors.forename: Eva L
authors.initials: EL
authors.lastname: Lund
authors.forename: Paul E G
authors.initials: PE
authors.lastname: Kristjansen
mesh_terms: D042682:Angiopoietins / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D003094:Collagen / Q000494:pharmacology; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D011509:Proteoglycans / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D042682:Angiopoietins; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; C118117:angiopoietin 4; D016222:Fibroblast Growth Factor 2; C059485:matrigel; D003094:Collagen