The innate immunity system plays a critical role in vascular repair and restenosis development. Liposomes encapsulating bisphosphonates (LipBPs), but not free BPs, suppress neointima formation following vascular injury mediated in part by monocytes. The objective of this study was to elucidate the role of monocyte subpopulations on vascular healing following LipBP treatment. The potency- and dose-dependent treatment effect of clodronate (CLOD) and alendronate (ALN) liposomes on restenosis inhibition, total monocyte depletion, and monocytes subpopulation was studied. Rats subjected to carotid injury were treated by a single IV injection of LipBPs at the time of injury. Low- and high-dose LipALN treatment (3 and 10 mg/kg, respectively) resulted in a dose-dependent effect on restenosis development after 30 days. Both doses of LipALN resulted in a dose-dependent inhibition of restenosis, but only high dose of LipALN depleted monocytes (−60.1 ± 4.4%, 48 h post injury). Although LipCLOD treatment (at an equivalent potency to 3 mg/kg alendronate) significantly reduced monocyte levels (72.1 ± 6%), no restenosis inhibition was observed. The major finding of this study is the correlation found between monocyte subclasses and restenosis inhibition. Non-classical monocyte (NCM) levels were found higher in LipALN-treated rats, but lower in LipCLOD-treated rats, 24 h after injury and treatment. We suggest that the inhibition of circulating monocyte subpopulations is the predominant mechanism by which LipBPs prevent restenosis. The effect of LipBP treatment on the monocyte subpopulation correlates with the dose and potency of LipBPs.
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GG is grateful to the Woll Sisters and Brothers Chair in Cardiovascular Diseases.
The protocol for this study was approved by the Institutional Committee for Animal Care and Use of the Hebrew University of Jerusalem.
All institutional and national guidelines for the care and use of laboratories animals were followed.
Conflict of interest
The authors declare that they have no conflict of interest.
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Grad, E., Zolotarevsky, K., Danenberg, H.D. et al. The role of monocyte subpopulations in vascular injury following partial and transient depletion. Drug Deliv. and Transl. Res. 8, 945–953 (2018). https://doi.org/10.1007/s13346-017-0404-5
- Monocytes subpopulation
- Vascular injury