title: Tetrahydrobiopterin determines vascular remodeling through enhanced endothelial cell survival and regeneration.
abstract: BACKGROUND
  Endothelial cell (EC) survival and regeneration are important determinants of the response to vascular injury that leads to neointimal hyperplasia and accelerated atherosclerosis. Nitric oxide (NO) is a key regulator of EC and endothelial progenitor cell function, but the pathophysiological mechanisms that regulate endothelial NO synthase in endothelial regeneration remain unclear.
  
  
  RESULTS
  Endothelium-targeted overexpression of GTP cyclohydrolase (GCH) I increased levels of the endothelial NO synthase cofactor, tetrahydrobiopterin, in an EC-specific manner and reduced neointimal hyperplasia in experimental vein grafts in GCH/apolipoprotein E-knockout mice. These effects were mediated through enhanced donor-derived survival and recipient-derived repopulation of GCH transgenic ECs, revealed by tracking studies in Tie2-LacZ/GCH-Tg/apolipoprotein E-knockout recipient mice or donor grafts, respectively. Endothelial GCH overexpression increased endothelial NO synthase coupling and enhanced the proliferative capacity of ECs and circulating endothelial progenitor cell numbers after vascular injury.
  
  
  CONCLUSIONS
  These observations indicate that endothelial tetrahydrobiopterin availability modulates neointimal hyperplasia after vascular injury via accelerated EC repopulation and growth. Targeting tetrahydrobiopterin-dependent endothelial NO synthase regulation in the endothelium is a rational therapeutic target to enhance endothelial regeneration and reduce neointimal hyperplasia in vascular injury states.
authors.affiliation: Center for Interventional Vascular Therapy, Division of Cardiology, New York Presbyterian Hospital and Columbia University, New York, NY; Cardiovascular Research Foundation, New York, NY; Department of Cardiovascular Medicine, John Radcliffe Hospital and University of Oxford, Oxford, United Kingdom.
authors.forename: Ziad A
authors.initials: ZA
authors.lastname: Ali
authors.affiliation: Department of Cardiovascular Medicine, John Radcliffe Hospital and University of Oxford, Oxford, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: Rinze
authors.affiliation: Department of Cardiovascular Medicine, John Radcliffe Hospital and University of Oxford, Oxford, United Kingdom.
authors.forename: Gillian
authors.initials: G
authors.lastname: Douglas
authors.affiliation: Cardiovascular Division, King's College Hospital, London, United Kingdom.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Cardiovascular Division, King's College Hospital, London, United Kingdom.
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: Center for Interventional Vascular Therapy, Division of Cardiology, New York Presbyterian Hospital and Columbia University, New York, NY.
authors.forename: Wei
authors.initials: W
authors.lastname: Qi
authors.affiliation: Department of Cardiovascular Medicine, John Radcliffe Hospital and University of Oxford, Oxford, United Kingdom.
authors.forename: Eileen
authors.initials: E
authors.lastname: McNeill
authors.affiliation: Department of Cardiovascular Medicine, John Radcliffe Hospital and University of Oxford, Oxford, United Kingdom.
authors.forename: Christina
authors.initials: C
authors.lastname: Bursill
authors.affiliation: Center for Interventional Vascular Therapy, Division of Cardiology, New York Presbyterian Hospital and Columbia University, New York, NY.
authors.forename: Isaac
authors.initials: I
authors.lastname: George
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors.forename: David R
authors.initials: DR
authors.lastname: Greaves
authors.affiliation: Cardiovascular Division, King's College Hospital, London, United Kingdom.
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Cardiovascular Medicine, John Radcliffe Hospital and University of Oxford, Oxford, United Kingdom.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Channon
mesh_terms: D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000502:physiology; D002470:Cell Survival / Q000502:physiology*; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology*; D006801:Humans; D006965:Hyperplasia / Q000473:pathology / Q000601:surgery; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058426:Neointima / Q000473:pathology / Q000601:surgery; D012038:Regeneration / Q000502:physiology*; D019737:Transplants; D015854:Up-Regulation / Q000502:physiology*; D014682:Vena Cava, Inferior / Q000166:cytology / Q000502:physiology
chemical_list: D001708:Biopterins; C003402:sapropterin
keywords: endothelial cells; endothelial progenitor cells; free radicals; nitric oxide synthase; remodeling
references.citation: N Engl J Med. 2003 Feb 13;348(7):593-600
references.pmid: 12584367
references.citation: Circ Res. 2003 Oct 17;93(8):e76-86
references.pmid: 14512446
references.citation: Blood. 2004 Dec 1;104(12):3591-7
references.pmid: 15161665
references.citation: Neuropsychobiology. 1994;29(2):53-6
references.pmid: 8170525
references.citation: Arterioscler Thromb Vasc Biol. 2006 Oct;26(10):2244-51
references.pmid: 16902164
references.citation: Circ Res. 2006 Jun 9;98(11):1405-13
references.pmid: 16645141
references.citation: J Physiol. 2005 Nov 1;568(Pt 3):1057-65
references.pmid: 16141271
references.citation: J Am Coll Cardiol. 1990 Jun;15(7):1667-87
references.pmid: 2188991
references.citation: Circulation. 2004 Jan 20;109(2):220-6
references.pmid: 14691039
references.citation: Hematol Oncol. 1998 Jun;16(2):57-67
references.pmid: 10065113
references.citation: Arterioscler Thromb Vasc Biol. 2003 Feb 1;23(2):176-82
references.pmid: 12588756
references.citation: Nat Med. 2003 Nov;9(11):1370-6
references.pmid: 14556003
references.citation: J Clin Invest. 2003 Sep;112(5):725-35
references.pmid: 12952921
references.citation: Circ Res. 2007 Oct 12;101(8):830-8
references.pmid: 17704208
references.citation: Biochem Biophys Res Commun. 2001 Nov 30;289(2):358-62
references.pmid: 11716480
references.citation: Circulation. 2004 Oct 5;110(14):1933-9
references.pmid: 15466656
references.citation: Arterioscler Thromb Vasc Biol. 2004 Mar;24(3):413-20
references.pmid: 14656731
references.citation: Arterioscler Thromb Vasc Biol. 2002 Oct 1;22(10):1567-72
references.pmid: 12377731
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3058-63
references.pmid: 9096345
references.citation: Arterioscler Thromb Vasc Biol. 2004 Mar;24(3):445-50
references.pmid: 14707037
references.citation: Prog Cardiovasc Dis. 1991 Jul-Aug;34(1):45-68
references.pmid: 2063013
references.citation: Am J Pathol. 2000 Aug;157(2):659-69
references.pmid: 10934168
references.citation: Circulation. 2007 Jul 10;116(2):163-73
references.pmid: 17592079
references.citation: Am J Pathol. 1998 Oct;153(4):1301-10
references.pmid: 9777962
references.citation: Neuroscience. 2006 Jul 21;140(4):1253-63
references.pmid: 16650618
references.citation: Circulation. 2003 Jun 24;107(24):3059-65
references.pmid: 12810616
references.citation: Cardiovasc Res. 2006 Apr 1;70(1):61-9
references.pmid: 16448633