Systemic Depletion of Macrophages by Liposomal Bisphosphonates Reduces Neointimal Formation Following Balloon-Injury in the Rat Carotid Artery

Haim D. Danenberg*, Ilia Fishbein, Hila Epstein, Johannes Waltenberger, Evgeny Moerman, Jukka Mönkkönen, Jianchuan Gao, Irith Gathi, Reuven Reichi, Gershon Golomb

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

Objectives: Macrophage depletion by liposomal clodronate inhibits neointimal formation after balloon-injury. The present study examined bisphosphonates (BPs) potency-effect relationship and the role of systemic versus local monocytes in vascular repair. Methods and Results: Liposomal preparations of clodronate, pamidronate, alendronate, and ISA-13-1 inhibited RAW-264 macrophages growth in a dose-response manner. Administration to balloon-injured rats suppressed neointimal growth. Neointima to media ratio (N/M) at 14 days was reduced from 1.35 ± 0.22 (control) to 0.4 ± 0.1 and 0.9 ± 0.17 by liposomal alendronate (1.5 mg/kg, i.v.) and liposomal ISA-13-1 (15 mg/kg), respectively (n = 8-10, P < 0.05). Suppression of neointimal formation was preserved at 30 days. Subcutaneous administration of liposomal BP (LBP) was also effective in suppressing neointimal formation, while short local intraluminal application had no effect. Immunostaining for ED-1 and ED-2 revealed no resident macrophages in the arterial wall, and reduced macrophage infiltration in LBP-treated animals. Arterial PDGF- B chain and PDGF-β receptor activation were reduced in LBP-treated animals and up-regulation of the PDGF receptor was noted. Conclusions: Systemic transient inactivation of monocytes and macrophages by LBPs reduced macrophage infiltration and neointimal formation in the rat carotid injury model. The findings demonstrate a BP potency-effect relationship, and highlight the role of circulating monocytes in vascular injury and repair.

Original languageEnglish
Pages (from-to)671-679
Number of pages9
JournalJournal of Cardiovascular Pharmacology
Volume42
Issue number5
DOIs
StatePublished - Nov 2003

Keywords

  • Balloon-injury
  • Bisphosphonates
  • Macrophages
  • Monocytes
  • Vascular-repair

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