Bolus Endovascular PDGFR-β Antisense Treatment Suppressed Intimal Hyperplasia in a Rat Carotid Injury Model

Abstract

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-β (PDGFR-β) 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-β in injured rat carotid arteries would be sufficient to prevent intimal hyperplasia and how it might contribute to the vascular healing process. Methods and Results —A bolus of antisense PDGFR-β delivered into injured rat carotid arteries reduced PDGFR-β 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-β 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-β to injured rat carotids reduced intimal hyperplasia, improved the reendothelialization process, and led to the recovery of endothelium-dependent regulation of vascular tone.