Bolus endovascular PDGFR-beta antisense treatment suppressed intimal hyperplasia in a rat carotid injury model.
BACKGROUND
Intimal thickening in accelerated arteriopathies relies on the migration of medial vascular smooth muscle cells (VSMCs) and their proliferation within the neointima. Activation of platelet-derived growth factor receptor-beta (PDGFR-beta) expressed in injured VSMCs is responsible for the migration of medial VSMCs to the intima. In the present study, we wanted to assess whether a single local endovascular delivery of antisense PDGFR-beta in injured rat carotid arteries would be sufficient to prevent intimal hyperplasia and how it might contribute to the vascular healing process.


RESULTS
A bolus of antisense PDGFR-beta delivered into injured rat carotid arteries reduced PDGFR-beta protein overexpression by >90% from day 3 to 28 after injury. At day 28 after injury, compared with injured untreated carotids, treatment with antisense PDGFR-beta reduced intimal hyperplasia by 58% and medial VSMC migration by 49% and improved vascular reendothelialization by 100% and vascular reactivity (EC(50)) to acetylcholine by 5-fold.


CONCLUSIONS
A single-bolus luminal delivery of antisense PDGFR-beta to injured rat carotids reduced intimal hyperplasia, improved the reendothelialization process, and led to the recovery of endothelium-dependent regulation of vascular tone.
Noiseux
N
N
Montreal Heart Institute and Department of Pharmacology, University of Montreal, Montreal, Québec, Canada.
Boucher
C H
CH
Cartier
R
R
Sirois
M G
MG
D000818:Animals; D002340:Carotid Artery Diseases / Q000473:pathology*; D017536:Carotid Artery, Common / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002452:Cell Count; D002455:Cell Division; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D006965:Hyperplasia; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007261:Infusions, Intra-Arterial; D008297:Male; D009119:Muscle Contraction; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000737:chemistry / Q000378:metabolism*; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology*; D017540:Tunica Media / Q000378:metabolism / Q000473:pathology*
D016376:Oligonucleotides, Antisense; D020797:Receptor, Platelet-Derived Growth Factor beta