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 (EC50) 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.