title: Influence of exercise training on proangiogenic TIE-2 monocytes and circulating angiogenic cells in patients with peripheral arterial disease.
abstract: BACKGROUND
  Inflammation is the driving force in atherosclerosis. One central strategy in the treatment of peripheral arterial disease (PAD) is the promotion of angiogenesis. Here, proangiogenic Tie-2 expressing monocytes (TEM) and circulating angiogenic cells (CAC) play a crucial role. Exercise training (ET) is recommended in PAD patients at Fontaine stage II to promote angiogenesis.
  
  
  METHODS
  40 patients with intermittend claudication (IC) [2 groups: supervised ET (SET) vs. non-supervised ET (nSET), each n = 20] and 20 healthy controls were included in the study. Analysis of TEM and CAC was performed from whole blood by flow-cytometry. TEM were identified via CD45, CD86, CD14, CD16 and analysed for the expression of Tie-2. CAC were identified via their expression of CD45 (CD45dim), CD34 and VEGF-R2 (CD309/KDR). Follow up was performed after mean of 7.65 ± 1.62 months.
  
  
  RESULTS
  In comparison to healthy controls, we found increased proportions of CAC (p < 0.0001) and similar TEM numbers in both ET groups. At follow-up (FU) TEM poroportions increased (p < 0.001) and CAC proportions decreased (p < 0.01), but both more significantly in SET (p < 0.001) than nSET (p = 0.01). Only in SET fibrinogen levels decreased and VEGF-A increased (both p < 0.05). Finally, we found in both ET groups a significant increase in absolute walking distance but with a higher individual increase in SET (p < 0.01). TEM and CAC proportions correlated inversely with the absolute walking distance (CAC: r = -0.296, p = 0.02; TEM: r = -0.270, p = 0.04) as well as with ABI (CAC: r = -0.394, p < 0.01; TEM: r = -0.382, p < 0.01).
  
  
  CONCLUSIONS
  ET influences the distribution of CAC and TEM proportions. nSET, although still effective in regard to an improved walking distance, is less effective in the influence of proangiogenic cells and inflammatory burden than SET. Our results indicate SET to be a more preferential exercise form, supporting the necessity to establish more SET programs.
authors.affiliation: Center of Cardiology, University Medical Center, Johannes-Gutenberg University, Langenbeckstr Str. 1, D-55101, Mainz, Germany. dopheide@uni-mainz.de.
authors.forename: Jörn F
authors.identifier: http://orcid.org/0000-0003-3365-8338
authors.initials: JF
authors.lastname: Dopheide
authors.affiliation: Center of Cardiology, University Medical Center, Johannes-Gutenberg University, Langenbeckstr Str. 1, D-55101, Mainz, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Geissler
authors.affiliation: Center of Cardiology, University Medical Center, Johannes-Gutenberg University, Langenbeckstr Str. 1, D-55101, Mainz, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rubrech
authors.affiliation: Center of Cardiology, University Medical Center, Johannes-Gutenberg University, Langenbeckstr Str. 1, D-55101, Mainz, Germany.
authors.forename: Amelie
authors.initials: A
authors.lastname: Trumpp
authors.affiliation: Department of Internal Medicine I, University Medical Center, Johannes-Gutenberg University, Langenbeckstr Str. 1, D-55101, Mainz, Germany.
authors.forename: Geraldine C
authors.initials: GC
authors.lastname: Zeller
authors.affiliation: Center of Cardiology, University Medical Center, Johannes-Gutenberg University, Langenbeckstr Str. 1, D-55101, Mainz, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
authors.affiliation: Center of Cardiology, University Medical Center, Johannes-Gutenberg University, Langenbeckstr Str. 1, D-55101, Mainz, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.affiliation: Department of Internal Medicine III, University Medical Center, Johannes-Gutenberg University, Langenbeckstr Str. 1, D-55101, Mainz, Germany.|Institute for Immunology, University Medical Center, Johannes-Gutenberg University, Langenbeckstr Str. 1, D-55101, Mainz, Germany.
authors.forename: Markus P
authors.initials: MP
authors.lastname: Radsak
authors.affiliation: Center of Cardiology, University Medical Center, Johannes-Gutenberg University, Langenbeckstr Str. 1, D-55101, Mainz, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Espinola-Klein
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood*; D005081:Exercise Therapy; D017079:Exercise Tolerance; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D007383:Intermittent Claudication / Q000097:blood / Q000175:diagnosis / Q000503:physiopathology / Q000628:therapy*; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D058729:Peripheral Arterial Disease / Q000097:blood / Q000175:diagnosis / Q000503:physiopathology / Q000628:therapy*; D010865:Pilot Projects; D042787:Receptor, TIE-2 / Q000097:blood*; D020127:Recovery of Function; D013997:Time Factors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D015415:Biomarkers; D018836:Inflammation Mediators; D008055:Lipids; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042787:Receptor, TIE-2
keywords: CAC; Exercise training; Inflammation; Peripheral arterial disease; TEM
references.citation: Blood. 2000 Feb 1;95(3):952-8
references.pmid: 10648408
references.citation: Circ Res. 2000 Sep 1;87(5):378-84
references.pmid: 10969035
references.citation: Cardiovasc Res. 2001 Feb 16;49(3):671-80
references.pmid: 11166280
references.citation: J Hematother Stem Cell Res. 2002 Feb;11(1):69-79
references.pmid: 11847004
references.citation: N Engl J Med. 2003 Feb 13;348(7):593-600
references.pmid: 12584367
references.citation: Circulation. 2004 Jan 20;109(2):220-6
references.pmid: 14691039
references.citation: Arterioscler Thromb Vasc Biol. 2004 Apr;24(4):684-90
references.pmid: 14988094
references.citation: Circ Res. 2004 Aug 20;95(4):343-53
references.pmid: 15321944
references.citation: Scand J Med Sci Sports. 2005 Feb;15(1):13-20
references.pmid: 15679567
references.citation: Eur J Cardiovasc Prev Rehabil. 2005 Aug;12(4):407-14
references.pmid: 16079651
references.citation: Cancer Cell. 2005 Sep;8(3):211-26
references.pmid: 16169466
references.citation: JAMA. 2006 Jan 11;295(2):180-9
references.pmid: 16403930
references.citation: Circulation. 2006 Mar 21;113(11):e463-654
references.pmid: 16549646
references.citation: Cochrane Database Syst Rev. 2006 Apr 19;(2):CD005263
references.pmid: 16625633
references.citation: Blood. 2007 Mar 1;109(5):1801-9
references.pmid: 17053059
references.citation: Eur J Vasc Endovasc Surg. 2007;33 Suppl 1:S1-75
references.pmid: 17140820
references.citation: Blood. 2007 Jun 15;109(12):5276-85
references.pmid: 17327411
references.citation: J Immunol. 2007 Jun 1;178(11):7405-11
references.pmid: 17513791
references.citation: J Immunol. 2008 Apr 1;180(7):5141-8
references.pmid: 18354240
references.citation: J Leukoc Biol. 2008 Nov;84(5):1271-8
references.pmid: 18664531
references.citation: J Thromb Haemost. 2009 Jul;7 Suppl 1:49-52
references.pmid: 19630767
references.citation: Cytometry A. 2009 Oct;75(10):848-53
references.pmid: 19739088
references.citation: J Intern Med. 2010 Apr;267(4):385-93
references.pmid: 19754853
references.citation: J Appl Physiol (1985). 2009 Dec;107(6):1943-50
references.pmid: 19797690
references.citation: J Gen Intern Med. 2010 Apr;25(4):284-90
references.pmid: 20131023
references.citation: Antioxid Redox Signal. 2011 Aug 15;15(4):967-80
references.pmid: 20812875
references.citation: PLoS One. 2010 Nov 03;5(11):e13790
references.pmid: 21072182
references.citation: Atherosclerosis. 2011 Jul;217(1):240-8
references.pmid: 21481871
references.citation: Eur Heart J. 2011 Nov;32(22):2851-906
references.pmid: 21873417
references.citation: Immunobiology. 2012 Dec;217(12):1273-84
references.pmid: 22898391
references.citation: Clin Res Cardiol. 2013 Apr;102(4):249-57
references.pmid: 23117697
references.citation: Circulation. 2013 Apr 2;127(13):1425-43
references.pmid: 23457117
references.citation: Compr Physiol. 2012 Oct;2(4):2933-3017
references.pmid: 23720270
references.citation: Microcirculation. 2014 Feb;21(2):148-58
references.pmid: 24125396
references.citation: Clin Res Cardiol. 2015 Sep;104(9):751-63
references.pmid: 25772524
references.citation: Clin Res Cardiol. 2015 Nov;104(11):982-9
references.pmid: 25967155
references.citation: Angiogenesis. 2016 Jan;19(1):67-78
references.pmid: 26462497
references.citation: JAMA. 1995 Sep 27;274(12):975-80
references.pmid: 7674529
references.citation: Adv Exp Med Biol. 1995;378:75-8
references.pmid: 8526149
references.citation: Proc Natl Acad Sci U S A. 1996 Mar 19;93(6):2588-92
references.pmid: 8637918
references.citation: Science. 1997 Feb 14;275(5302):964-7
references.pmid: 9020076
references.citation: N Engl J Med. 1999 Jan 14;340(2):115-26
references.pmid: 9887164