Systemic depletion of macrophages by liposomal bisphosphonates reduces neointimal formation following balloon-injury in the rat carotid artery.
OBJECTIVE
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.


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-beta 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.
Danenberg
Haim D
HD
Department of Cardiology, Hadassah-Hebrew University Hospital, Jerusalem, Israel. danen@mit.edu
Fishbein
Ilia
I
Epstein
Hila
H
Waltenberger
Johannes
J
Moerman
Evgeny
E
Mönkkönen
Jukka
J
Gao
Jianchuan
J
Gathi
Irith
I
Reichi
Reuven
R
Golomb
Gershon
G
D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D017536:Carotid Artery, Common / Q000187:drug effects* / Q000473:pathology; D002460:Cell Line; D004164:Diphosphonates / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D007165:Immunosuppression Therapy / Q000379:methods; D008081:Liposomes; D008264:Macrophages / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D051381:Rats; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology
D004164:Diphosphonates; D008081:Liposomes