Flow-dependent regulation of angiopoietin-2.
Endothelial cells are constantly exposed to high or low shear stress in arteries and veins by the flowing blood. Angiopoietin-2 (Ang-2) is acting as a critical regulator of vessel maturation and endothelial cell quiescence. In this study, flow-dependent regulation of Ang-2 was analyzed in vitro and in vivo. Ang-2 mRNA, protein expression and release was upregulated by 24 h of low (1 dyne/cm(2)), but downregulated by high flow (30 dyne/cm(2)) in human endothelial cells. Increased endothelial NO synthase expression and NO formation was not affecting regulation of Ang-2 by low or high flow. Low and high flow increased VEGF-A expression. Inhibition of VEGFR-2 prevented upregulation of Ang-2 by low flow, but not downregulation of Ang-2 by high flow. Furthermore, upregulation of Ang-2 by VEGF was reduced by application of high flow. Forkhead box O (FOXO) transcription factor FOXO1 has been shown to regulate Ang-2 expression in endothelial cells. FOXO1 binding activity was reduced by high flow. Nuclear localization of transcription factor FOXO1 was not changed by low flow, but reduced by high flow. In vivo, Ang-2 was higher expressed in veins compared to arteries. Arterial ligation augmented Ang-2 expression in distal arterial low flow areas. Our results support a VEGF-dependent induction of Ang-2 in low flow areas, and FOXO1-dependent downregulation of Ang-2 in high flow areas. These data suggest a new mechanism of flow-dependent regulation of vessel stability and differentiation.
Goettsch
Winfried
W
Department of Vascular Endothelium and Microcirculation, University of Technology, Dresden, Germany.
Gryczka
Corina
C
Korff
Thomas
T
Ernst
Evelyn
E
Goettsch
Claudia
C
Seebach
Jochen
J
Schnittler
Hans-Joachim
HJ
Augustin
Hellmut G
HG
Morawietz
Henning
H
D042683:Angiopoietin-1 / Q000494:pharmacology; D042702:Angiopoietin-2 / Q000378:metabolism*; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D002469:Cell Separation / Q000379:methods; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D016895:Culture Media, Serum-Free; D003609:Dactinomycin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005263:Femoral Artery / Q000502:physiology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000032:analysis; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors; D009573:Nitrites / Q000032:analysis; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D042787:Receptor, TIE-2 / Q000378:metabolism; D012039:Regional Blood Flow; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction / Q000187:drug effects; D013314:Stress, Mechanical; D014226:Triazenes / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
C105351:1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D016227:Benzoquinones; D002867:Chromones; D016895:Culture Media, Serum-Free; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D047029:Lactams, Macrocyclic; D009025:Morpholines; D009573:Nitrites; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D014226:Triazenes; D042461:Vascular Endothelial Growth Factor A; D003609:Dactinomycin; D017828:Rifabutin; D009569:Nitric Oxide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C020754:herbimycin; D052250:Nitric Oxide Synthase Type III; D011505:Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D019331:NG-Nitroarginine Methyl Ester