Abstract
Aims
The mechanisms of monocyte recruitment to arteriogenic collaterals are largely unknown. We investigated the role of chemokine (C-X-C-motif) ligand 1 (CXCL1) and its cognate receptor, chemokine (C-X-C-motif) receptor 2 (CXCR2) in arteriogenesis.
Methods and results
After femoral artery ligation in Sprague–Dawley rats, either native collaterals were harvested or placebo, CXCL1 or CXCR2 blocker was administered via an osmopump. Perfusion recovery was measured with Laser Doppler, leukocyte populations were analyzed by fluorescence-activated cell sorting, and hind limb sections were stained for macrophage marker cluster of differentiation 68 (CD68). In vitro, fluorescent CXCL1 or human acute monocytic leukemia cell line (THP-1) monocytic cells were flown over shear-stressed endothelium. CXCL1 mRNA expression in collaterals was dramatically upregulated already 1 h after ligation (ratio ligated/sham 5.73). CD68 mRNA was upregulated from 12 h until 3 days after ligation (peak ratio ligated/sham 2.65). CXCL1 treatment augmented perfusion recovery at 3 and 7 days (p < 0.05) after ligation, and a significant increase in the number of peri-collateral macrophages was evident concomitantly (p < 0.05). Conversely, CXCR2 antagonist treatment caused a decrease in perfusion recovery both at 7 and 10 days postligation (p = 0.01) and also significantly reduced the number of peri-collateral macrophages (p < 0.05). In vitro, CXCL1 tethered to and was taken up by endothelial cells under shear stress conditions and enhanced THP-1 adherence compared to control (p < 0.05). In contrast, CXCR2 antagonist compromised THP-1 adherence to endothelial cells (p < 0.05).
Conclusion
CXCL1 presented on the luminal endothelial surface leads to an increase in the number of peri-collateral macrophages, thus improving the arteriogenic response after arterial ligation.
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Abbreviations
- CXCL1:
-
(C-X-C-motif) ligand 1
- CXCR2:
-
(C-X-C-motif) receptor 2
- THP-1:
-
Human acute monocytic leukemia cell line
- CD68:
-
Cluster of differentiation 68
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Acknowledgments
This work was supported by CTMM, the Center for Translational Molecular Medicine (www.ctmm.nl) project EMINENCE [Grant No. 01C-204].
Conflict of interest
The authors declare that they have no conflict of interest.
Compliance with Ethical Standards
Experiments were conducted according to the Guide for the Care and Use of Laboratory Animals published by the USA National Institutes of Health and were approved by the institutional Ethics Committee on Experimental Animal Welfare.
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Vries, M.H.M., Wagenaar, A., Verbruggen, S.E.L. et al. CXCL1 promotes arteriogenesis through enhanced monocyte recruitment into the peri-collateral space. Angiogenesis 18, 163–171 (2015). https://doi.org/10.1007/s10456-014-9454-1
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DOI: https://doi.org/10.1007/s10456-014-9454-1