Hypercholesterolemia Promotes P-Selectin–Dependent Platelet–Endothelial Cell Adhesion in Postcapillary Venules

Abstract

Objective— The objectives of this study were to determine whether hypercholesterolemia promotes platelet–endothelial cell (P/E) adhesion in murine postcapillary venules and define the contributions of endothelial or platelet associated P-selection to hypercholesterolemia-induced P/E interactions. Methods and Results— Wild-type (WT) or P-selectin deficient (P-sel^−/−) platelets were isolated and labeled with the fluorochrome CFSE and administered to either WT or P-sel^−/− mice placed on a normal diet (ND) or high cholesterol diet (HCD). Intravital videomicroscopy was used to quantify platelet saltation and firm adhesion. HCD-WT mice exhibited a time-dependent increase in P/E cell interactions (relative to ND-WT). Flow cytometry revealed an increased expression of P-selectin on circulating platelets of HCD-WT mice at 2 weeks compared with ND-WT mice. When WT platelets were monitored in HCD-P-sel^−/− mice, P/E adhesion was dramatically reduced. However, when P-sel^−/− platelets were monitored in HCD-WT recipients, P/E adhesive interactions were reduced even further, comparable to ND-WT mice. Conclusions— These results indicate that elevated cholesterol levels promote P/E adhesion in postcapillary venules and that whereas both endothelial and platelet P-selectin contribute to hypercholesterolemia-induced recruitment of platelets, platelet-associated P-selectin seems to play a more important role in producing the prothrombogenic phenotype in venules.