title: Absence of chemokine (C-x-C motif) ligand 10 diminishes perfusion recovery after local arterial occlusion in mice.
abstract: OBJECTIVE
  In arteriogenesis, pre-existing anastomoses undergo enlargement to restore blood flow in ischemic tissues. Chemokine (C-X-C motif) ligand 10 (CXCL10) is secreted after Toll-like receptor activation. Toll-like receptors are involved in arteriogenesis; however, the role of CXCL10 is still unclear. In this study, we investigated the role for CXCL10 in a murine hindlimb ischemia model.
  
  
  RESULTS
  Unilateral femoral artery ligation was performed in wild-type (WT) and CXCL10(-/-) knockout (KO) mice and perfusion recovery was measured using laser-Doppler perfusion analysis. Perfusion recovery was significantly lower in KO mice compared with WT at days 4 and 7 after surgery (KO versus WT: 28±5% versus 81±13% at day 4; P=0.003 and 57±12% versus 107±8% at day 7; P=0.003). Vessel measurements of α-smooth muscle actin-positive vessels revealed increasing numbers in time after surgery, which was significantly higher in WT when compared with that in KO. Furthermore, α-smooth muscle actin-positive vessels were significantly larger in WT when compared with those in KO at day 7 (wall thickness, P<0.001; lumen area, P=0.003). Local inflammation was assessed in hindlimb muscles, but this did not differ between WT and KO. Chimerization experiments analyzing perfusion recovery and histology revealed an equal contribution for bone marrow-derived and circulating CXCL10. Migration assays showed a stimulating role for both intrinsic and extrinsic CXCL10 in vascular smooth muscle cell migration.
  
  
  CONCLUSIONS
  CXCL10 plays a causal role in arteriogenesis. Bone marrow-derived CXCL10 and tissue-derived CXCL10 play a critical role in accelerating perfusion recovery after arterial occlusion in mice probably by promoting vascular smooth muscle cell recruitment and maturation of pre-existing anastomoses.
authors.affiliation: From the Laboratory of Experimental Cardiology (P.v.d.B., R.T.H., I.E.H., G.P., D.P.V.d.K.), Department of Nephrology and Hypertension (C.C.), and Department of Cardiology (H.J.D.), University Medical Center Utrecht, Utrecht, The Netherlands; Molecular Cardiology Laboratory, Experimental Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands (M.M.B., C.C.); Department of Surgery (P.H.A.Q.) and Einthoven Laboratory of Experimental Vascular Medicine (P.H.A.Q.), Leiden University Medical Center, Leiden, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands (I.E.H., G.P., D.P.V.d.K.); and Cardiovascular Research Institute and Surgery, National University Hospital, Singapore, Singapore (D.P.V.d.K.).
authors.forename: Pleunie
authors.initials: P
authors.lastname: van den Borne
authors.forename: René T
authors.initials: RT
authors.lastname: Haverslag
authors.forename: Maarten M
authors.initials: MM
authors.lastname: Brandt
authors.forename: Caroline
authors.initials: C
authors.lastname: Cheng
authors.forename: Henricus J
authors.initials: HJ
authors.lastname: Duckers
authors.forename: Paul H A
authors.initials: PH
authors.lastname: Quax
authors.forename: Imo E
authors.initials: IE
authors.lastname: Hoefer
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
authors.forename: Dominique P V
authors.initials: DP
authors.lastname: de Kleijn
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D001853:Bone Marrow / Q000378:metabolism; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000037:antagonists & inhibitors / Q000097:blood / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D003097:Collateral Circulation / Q000502:physiology*; D005260:Female; D005263:Femoral Artery; D006614:Hindlimb / Q000098:blood supply; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation; D007511:Ischemia / Q000503:physiopathology; D017078:Laser-Doppler Flowmetry; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D011828:Radiation Chimera; D011994:Recombinant Proteins / Q000494:pharmacology; D015427:Reperfusion Injury / Q000503:physiopathology*
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D034741:RNA, Small Interfering; D011994:Recombinant Proteins
keywords: cell movement; chemokine CXCL10; inflammation; interferon-γ-inducible protein of 10 kDa; myocytes, smooth muscle