Intimal hyperplasia recurs after removal of PDGF-AB and -BB inhibition in the rat carotid artery injury model.
Several antagonists specific for platelet-derived growth factor (PDGF) or its receptors have recently been developed and shown to inhibit intimal hyperplasia formation in various animal models, but data investigating the durability of this intervention is limited. The present study was designed to investigate the potency of PDGF B-chain aptamer, a novel type of PDGF-AB and -BB antagonist, in the rat carotid model and to characterize intermediate-term effects on lesion formation. One hundred thirty-four animals were randomized to aptamer treatment or placebo. Daily treatment with the antagonist resulted in a 50% reduction in lesion size at 2 weeks (P<0.001). The beneficial effect involved increased apoptosis and possibly an interference with smooth muscle cell migration. Discontinuing administration 1 week earlier did not give any significant benefit compared with phosphate-buffered saline-treated controls. When the antagonist was administered for 2 weeks and the vessels analyzed 6 weeks later, the beneficial effect was lost and the treated lesions had a higher intima-media and area-cell ratio compared with the treated lesions in the 2-week-endpoint study. Our findings confirm a role of PDGF B-chain in intimal hyperplasia, but the successful use of PDGF antagonists may require either prolonged treatment or combination therapy with other agents.
Leppänen
O
O
Ludwig Institute for Cancer Research Department of Surgery, Uppsala, Sweden.
Janjic
N
N
Carlsson
M A
MA
Pietras
K
K
Levin
M
M
Vargeese
C
C
Green
L S
LS
Bergqvist
D
D
Ostman
A
A
Heldin
C H
CH
D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D000077214:Becaplermin; D001665:Binding Sites / Q000187:drug effects; D002339:Carotid Arteries / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006965:Hyperplasia; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D009841:Oligonucleotides / Q000378:metabolism / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012008:Recurrence; D017539:Tunica Intima / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
D009841:Oligonucleotides; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins; C095477:platelet-derived growth factor AB; D000077214:Becaplermin