Platelet CD40 Mediates Leukocyte Recruitment and Neointima Formation after Arterial Denudation Injury in Atherosclerosis-Prone Mice

Abstract

The role of platelets in the development of thrombosis and abrupt closure after angioplasty is well recognized. However, the direct impact of platelets on neointima formation after arterial injury remains undetermined. Herein, we show that neointima formation after carotid artery wire injury reduces markedly in CD40^-/- apolipoprotein E-deficient (apoE^-/-) mice but only slightly in CD40 ligand^-/-apoE^-/- mice, compared with apoE^-/- mice. Wild-type and CD40-deficient platelets were isolated from blood of apoE^-/- and CD40^-/-apoE^-/- mice, respectively. The i.v. injection of thrombin-activated platelets into CD40^-/-apoE^-/- mice was performed every 5 days, starting at 2 days before wire injury. Injection of wild-type platelets promoted neointima formation, which was associated with increased inflammation by stimulating leukocyte recruitment via up-regulation of circulating platelet surface P-selectin expression and the formation of platelet-leukocyte aggregates. It was also associated with further promoting the luminal deposition of platelet-derived regulated on activation normal T cell expressed and secreted/chemokine (C-C motif) ligand 5 and expression of monocyte chemoattractant protein-1 and vascular cell adhesion molecule 1 in wire-injured carotid arteries. Remarkably, all these inflammatory actions by activated platelets were abrogated by lack of CD40 on injected platelets. Moreover, injection of wild-type platelets inhibited endothelial recovery in wire-injured carotid arteries, but this effect was also abrogated by lack of CD40 on injected platelets. Results suggest that platelet CD40 plays a pivotal role in neointima formation after arterial injury and might represent an attractive target to prevent restenosis after vascular interventions.