title: Exercise promotes collateral artery growth mediated by monocytic nitric oxide.
abstract: OBJECTIVE
  Collateral artery growth (arteriogenesis) is an important adaptive response to hampered arterial perfusion. It is unknown whether preventive physical exercise before limb ischemia can improve arteriogenesis and modulate mononuclear cell function. This study aimed at investigating the effects of endurance exercise before arterial occlusion on MNC function and collateral artery growth.
  
  
  RESULTS
  After 3 weeks of voluntary treadmill exercise, ligation of the right femoral artery was performed in mice. Hindlimb perfusion immediately after surgery did not differ from sedentary mice. However, previous exercise improved perfusion restoration ≤7 days after femoral artery ligation, also when exercise was stopped at ligation. This was accompanied by an accumulation of peri-collateral macrophages and increased expression of endothelial nitric oxide synthase and inducible nitric oxide synthase (iNOS) in hindlimb collateral and in MNC of blood and spleen. Systemic monocyte and macrophage depletion by liposomal clodronate but not splenectomy attenuated exercise-induced perfusion restoration, collateral artery growth, peri-collateral macrophage accumulation, and upregulation of iNOS. iNOS-deficient mice did not show exercise-induced perfusion restoration. Transplantation of bone marrow-derived MNC from iNOS-deficient mice into wild-type animals inhibited exercise-induced collateral artery growth. In contrast to sedentary controls, thrice weekly aerobic exercise training for 6 months in humans increased peripheral blood MNC iNOS expression.
  
  
  CONCLUSIONS
  Circulating mononuclear cell-derived inducible nitric oxide is an important mediator of exercise-induced collateral artery growth.
authors.affiliation: From the Klinik für Innere Medizin III (S.H.S., D.N.M., C.W., L.S., A.D., S.I.B., M.B., U.L.) and Institut für Molekulare Zellbiologie (P.L.), Universitätsklinikum des Saarlandes, Homburg/Saar, Germany; Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, VUMC, Amsterdam, The Netherlands (N.R.); and Institut für Sport- und Präventivmedizin, Universität des Saarlandes, Saarbrücken, Germany (T.M.). Stephan.Schirmer@uks.eu.
authors.forename: Stephan H
authors.initials: SH
authors.lastname: Schirmer
authors.affiliation: From the Klinik für Innere Medizin III (S.H.S., D.N.M., C.W., L.S., A.D., S.I.B., M.B., U.L.) and Institut für Molekulare Zellbiologie (P.L.), Universitätsklinikum des Saarlandes, Homburg/Saar, Germany; Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, VUMC, Amsterdam, The Netherlands (N.R.); and Institut für Sport- und Präventivmedizin, Universität des Saarlandes, Saarbrücken, Germany (T.M.).
authors.forename: Dominic N
authors.initials: DN
authors.lastname: Millenaar
authors.affiliation: From the Klinik für Innere Medizin III (S.H.S., D.N.M., C.W., L.S., A.D., S.I.B., M.B., U.L.) and Institut für Molekulare Zellbiologie (P.L.), Universitätsklinikum des Saarlandes, Homburg/Saar, Germany; Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, VUMC, Amsterdam, The Netherlands (N.R.); and Institut für Sport- und Präventivmedizin, Universität des Saarlandes, Saarbrücken, Germany (T.M.).
authors.forename: Christian
authors.initials: C
authors.lastname: Werner
authors.affiliation: From the Klinik für Innere Medizin III (S.H.S., D.N.M., C.W., L.S., A.D., S.I.B., M.B., U.L.) and Institut für Molekulare Zellbiologie (P.L.), Universitätsklinikum des Saarlandes, Homburg/Saar, Germany; Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, VUMC, Amsterdam, The Netherlands (N.R.); and Institut für Sport- und Präventivmedizin, Universität des Saarlandes, Saarbrücken, Germany (T.M.).
authors.forename: Lisa
authors.initials: L
authors.lastname: Schuh
authors.affiliation: From the Klinik für Innere Medizin III (S.H.S., D.N.M., C.W., L.S., A.D., S.I.B., M.B., U.L.) and Institut für Molekulare Zellbiologie (P.L.), Universitätsklinikum des Saarlandes, Homburg/Saar, Germany; Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, VUMC, Amsterdam, The Netherlands (N.R.); and Institut für Sport- und Präventivmedizin, Universität des Saarlandes, Saarbrücken, Germany (T.M.).
authors.forename: Achim
authors.initials: A
authors.lastname: Degen
authors.affiliation: From the Klinik für Innere Medizin III (S.H.S., D.N.M., C.W., L.S., A.D., S.I.B., M.B., U.L.) and Institut für Molekulare Zellbiologie (P.L.), Universitätsklinikum des Saarlandes, Homburg/Saar, Germany; Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, VUMC, Amsterdam, The Netherlands (N.R.); and Institut für Sport- und Präventivmedizin, Universität des Saarlandes, Saarbrücken, Germany (T.M.).
authors.forename: Stephanie I
authors.initials: SI
authors.lastname: Bettink
authors.affiliation: From the Klinik für Innere Medizin III (S.H.S., D.N.M., C.W., L.S., A.D., S.I.B., M.B., U.L.) and Institut für Molekulare Zellbiologie (P.L.), Universitätsklinikum des Saarlandes, Homburg/Saar, Germany; Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, VUMC, Amsterdam, The Netherlands (N.R.); and Institut für Sport- und Präventivmedizin, Universität des Saarlandes, Saarbrücken, Germany (T.M.).
authors.forename: Peter
authors.initials: P
authors.lastname: Lipp
authors.affiliation: From the Klinik für Innere Medizin III (S.H.S., D.N.M., C.W., L.S., A.D., S.I.B., M.B., U.L.) and Institut für Molekulare Zellbiologie (P.L.), Universitätsklinikum des Saarlandes, Homburg/Saar, Germany; Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, VUMC, Amsterdam, The Netherlands (N.R.); and Institut für Sport- und Präventivmedizin, Universität des Saarlandes, Saarbrücken, Germany (T.M.).
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.affiliation: From the Klinik für Innere Medizin III (S.H.S., D.N.M., C.W., L.S., A.D., S.I.B., M.B., U.L.) and Institut für Molekulare Zellbiologie (P.L.), Universitätsklinikum des Saarlandes, Homburg/Saar, Germany; Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, VUMC, Amsterdam, The Netherlands (N.R.); and Institut für Sport- und Präventivmedizin, Universität des Saarlandes, Saarbrücken, Germany (T.M.).
authors.forename: Tim
authors.initials: T
authors.lastname: Meyer
authors.affiliation: From the Klinik für Innere Medizin III (S.H.S., D.N.M., C.W., L.S., A.D., S.I.B., M.B., U.L.) and Institut für Molekulare Zellbiologie (P.L.), Universitätsklinikum des Saarlandes, Homburg/Saar, Germany; Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, VUMC, Amsterdam, The Netherlands (N.R.); and Institut für Sport- und Präventivmedizin, Universität des Saarlandes, Saarbrücken, Germany (T.M.).
authors.forename: Michael
authors.initials: M
authors.lastname: Böhm
authors.affiliation: From the Klinik für Innere Medizin III (S.H.S., D.N.M., C.W., L.S., A.D., S.I.B., M.B., U.L.) and Institut für Molekulare Zellbiologie (P.L.), Universitätsklinikum des Saarlandes, Homburg/Saar, Germany; Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, VUMC, Amsterdam, The Netherlands (N.R.); and Institut für Sport- und Präventivmedizin, Universität des Saarlandes, Saarbrücken, Germany (T.M.).
authors.forename: Ulrich
authors.initials: U
authors.lastname: Laufs
mesh_terms: D000328:Adult; D000818:Animals; D016026:Bone Marrow Transplantation; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000097:blood / Q000235:genetics; D003097:Collateral Circulation; D004195:Disease Models, Animal; D015444:Exercise; D005260:Female; D006614:Hindlimb; D006801:Humans; D007511:Ischemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism* / Q000637:transplantation; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D005082:Physical Exertion; D034622:RNA Interference; D012039:Regional Blood Flow; D012420:Running; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse
keywords: bone marrow; collateral circulation; exercise; hindlimb; monocytes; nitric oxide; vascular growth