TY - JOUR
T1 - Systemic Depletion of Macrophages by Liposomal Bisphosphonates Reduces Neointimal Formation Following Balloon-Injury in the Rat Carotid Artery
AU - Danenberg, Haim D.
AU - Fishbein, Ilia
AU - Epstein, Hila
AU - Waltenberger, Johannes
AU - Moerman, Evgeny
AU - Mönkkönen, Jukka
AU - Gao, Jianchuan
AU - Gathi, Irith
AU - Reichi, Reuven
AU - Golomb, Gershon
PY - 2003/11
Y1 - 2003/11
N2 - 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.
AB - 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.
KW - Balloon-injury
KW - Bisphosphonates
KW - Macrophages
KW - Monocytes
KW - Vascular-repair
UR - http://www.scopus.com/inward/record.url?scp=10744222354&partnerID=8YFLogxK
U2 - 10.1097/00005344-200311000-00014
DO - 10.1097/00005344-200311000-00014
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C2 - 14576517
AN - SCOPUS:10744222354
SN - 0160-2446
VL - 42
SP - 671
EP - 679
JO - Journal of Cardiovascular Pharmacology
JF - Journal of Cardiovascular Pharmacology
IS - 5
ER -