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.

APPROACH AND 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: Pleunie van den Borne, René T Haverslag, Maarten M Brandt, Caroline Cheng, Henricus J Duckers, Paul H A Quax, Imo E Hoefer, Gerard Pasterkamp, Dominique P V de Kleijn
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 34 Issue 3 Pg. 594-602 (Mar 2014) ISSN: 1524-4636 [Electronic] United States
• PMID: 24407030 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CXCL10 protein, human
• Chemokine CXCL10
• Cxcl10 protein, mouse
• RNA, Small Interfering
• Recombinant Proteins

Topics

• Animals
• Aorta (cytology)
• Bone Marrow (metabolism)
• Cells, Cultured
• Chemokine CXCL10 (antagonists & inhibitors, blood, deficiency, genetics, pharmacology, physiology)
• Collateral Circulation (physiology)
• Female
• Femoral Artery
• Hindlimb (blood supply)
• Human Umbilical Vein Endothelial Cells
• Humans
• Inflammation
• Ischemia (physiopathology)
• Laser-Doppler Flowmetry
• Ligation
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Muscle, Skeletal (blood supply, metabolism)
• Muscle, Smooth, Vascular (pathology)
• Myocytes, Smooth Muscle (metabolism)
• Neovascularization, Physiologic (physiology)
• RNA Interference
• RNA, Small Interfering (pharmacology)
• Radiation Chimera
• Recombinant Proteins (pharmacology)
• Reperfusion Injury (physiopathology)