title: Vascular endothelial growth factor-A inhibits EphB4 and stimulates delta-like ligand 4 expression in adult endothelial cells.
abstract: BACKGROUND
  During vein graft adaptation to the arterial circulation, vascular endothelial growth factor (VEGF) A expression transiently increases before becoming downregulated; however, the role of VEGF-A in venous remodeling is not clear. In addition, although VEGF-A stimulates angiogenesis and determines arterial identity in nascent arterial endothelial cells (EC), the role of VEGF-A in regulating identity in adult venous EC is also not clear.
  
  
  METHODS
  EC, wild type (EphB4+/+) or heterozygous knockout (EphB4+/-), were stimulated with VEGF-A (0-100 ng/mL) and examined with quantitative polymerase chain reaction and western blotting.
  
  
  RESULTS
  VEGF-A (100 ng/mL) inhibited expression of EphB4 and stimulated expression of delta-like ligand 4 (dll4) but did not stimulate either notch or EphrinB2 expression in adult venous EC. Pretreatment with VEGF receptor 2-neutralizing antibody abolished VEGF-stimulated downregulation of EphB4 but not the upregulation of dll4. Pretreatment with PD98059 or wortmannin showed that VEGF-A downregulation of EphB4 and upregulation of dll4 are mitogen-activated protein kinase kinase and extracellular signal-regulated kinase dependent but phosphatidylinositol 3 kinase-Akt independent. Compared with VEGF-induced EphB4 downregulation and dll4 upregulation in control EC, reduced EphB4 signaling in EphB4+/- EC showed even further downregulation of EphB4 and upregulation of dll4.
  
  
  CONCLUSIONS
  Despite the genetic programming of arterial and venous EC fate, VEGF-A can repress venous identity in adult venous EC without induction of arterial identity. These changes in adult EC in vitro recapitulate the changes in identity described during vein graft adaptation to the arterial environment in vivo.
authors: Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, Connecticut 06520-8089, USA.
authors: Chenzi
authors: C
authors: Yang
authors: Yuanyuan
authors: Y
authors: Guo
authors: Caroline C
authors: CC
authors: Jadlowiec
authors: Xin
authors: X
authors: Li
authors: Wei
authors: W
authors: Lv
authors: Lynn S
authors: LS
authors: Model
authors: Michael J
authors: MJ
authors: Collins
authors: Yuka
authors: Y
authors: Kondo
authors: Akihito
authors: A
authors: Muto
authors: Chang
authors: C
authors: Shu
authors: Alan
authors: A
authors: Dardik
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism*; D036388:Ephrin-B2 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D036224:Receptor, EphB4 / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014680:Veins / Q000637:transplantation*
chemical_list: D036388:Ephrin-B2; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C064045:delta protein; D019869:Phosphatidylinositol 3-Kinases; D036224:Receptor, EphB4; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
references: FASEB J. 2002 Jul;16(9):1126-8
references: 12039842
references: Semin Cell Dev Biol. 2003 Apr;14(2):113-9
references: 12651094
references: PLoS Comput Biol. 2006 Dec 29;2(12):e180
references: 17196035
references: Cancer Res. 2006 Sep 1;66(17):8501-10
references: 16951162
references: J Clin Invest. 2005 Aug;115(8):2119-27
references: 16075056
references: Arterioscler Thromb Vasc Biol. 2009 Dec;29(12):2125-31
references: 19797707
references: J Virol. 1998 Apr;72(4):3221-6
references: 9525648
references: Mol Cell. 1999 Sep;4(3):403-14
references: 10518221
references: J Exp Med. 2011 Mar 14;208(3):561-75
references: 21339325
references: Science. 2003 Nov 28;302(5650):1575-7
references: 14645852
references: Cell Signal. 2007 Oct;19(10):2003-12
references: 17658244
references: Ann Vasc Dis. 2008;1(1):28-34
references: 23555335
references: J Vasc Surg. 1998 Jan;27(1):167-73
references: 9474095
references: Circulation. 2005 May 3;111(17):2210-8
references: 15851594
references: Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9349-54
references: 9689083
references: J Vasc Surg. 2006 Oct;44(4):863-70
references: 17012009
references: Circ Res. 2006 Sep 15;99(6):656-62
references: 16931799
references: Nature. 1996 Apr 4;380(6573):439-42
references: 8602242
references: Arterioscler Thromb Vasc Biol. 1998 Feb;18(2):227-34
references: 9484987
references: J Vasc Surg. 1986 Feb;3(2):204-15
references: 3511302
references: J Biol Chem. 2000 Jun 16;275(24):18040-5
references: 10748121
references: Curr Biol. 2006 Jul 11;16(13):1366-72
references: 16824925
references: Proc Natl Acad Sci U S A. 2001 May 8;98(10):5643-8
references: 11344305
references: Nature. 2005 May 5;435(7038):98-104
references: 15875024
references: Cell. 1993 Mar 26;72(6):835-46
references: 7681362
references: Cell. 1998 May 29;93(5):741-53
references: 9630219
references: Circ J. 2010 Aug;74(8):1501-12
references: 20606326
references: Ann Surg. 1986 Apr;203(4):339-45
references: 3516084
references: J Biol Chem. 2005 Mar 25;280(12):11185-91
references: 15668248
references: Mech Dev. 2001 Nov;109(1):115-9
references: 11677062
references: J Clin Invest. 2010 Apr;120(4):1217-28
references: 20237411
references: Arterioscler Thromb Vasc Biol. 2007 Jul;27(7):1562-71
references: 17463332
references: Circ Res. 2009 Mar 13;104(5):576-88
references: 19286613
references: Nature. 1996 Apr 4;380(6573):435-9
references: 8602241
references: J Surg Res. 2011 Nov;171(1):e149-60
references: 21872265
references: Development. 2001 Oct;128(19):3675-83
references: 11585794
references: Dev Cell. 2010 May 18;18(5):713-24
references: 20434959
references: Exp Cell Res. 2006 Mar 10;312(5):584-93
references: 16445911
references: Histol Histopathol. 2010 May;25(5):637-46
references: 20238301
references: Blood. 2006 Feb 1;107(3):931-9
references: 16219802
references: Dev Biol. 2001 Feb 15;230(2):151-60
references: 11161569
references: J Natl Cancer Inst. 2008 Jan 16;100(2):81-3
references: 18182614
references: Dev Cell. 2002 Jul;3(1):127-36
references: 12110173
references: Sci STKE. 2006 Oct 03;2006(355):pe39
references: 17018851