Role of platelets in hypercholesterolemia-induced leukocyte recruitment and arteriolar dysfunction

Objective: To define the contribution of platelets, specifically platelet-associated P-selectin, to the altered venular and arteriolar responses induced by hypercholesterolemia. Methods: Leukocyte and platelet recruitment in cremasteric venules, and endothelium-dependent relaxation (EDR) in arterioles were determined using intravital videomicroscopy. Wild-type (WT) mice were placed on a normal or high cholesterol diet. Hypercholesterolemic mice were treated with blocking antibodies against either P-selectin or PSGL-1, or were depleted of neutrophils (ANS) or platelets (APS). Bone marrow chimeras (P-selectin deficiency in platelets, but not in endothelial cells) were produced by transplanting bone marrow from P-selectin -/- into WT mice (P-sel -/- -> WT). Results: Hypercholesterolemia (HC) elicited the recruitment of adherent platelets and leukocytes in venules and an impaired EDR in arterioles. The exaggerated cell adhesion responses were absent in hypercholesterolemic mice treated with ANS, anti-P-selectin or anti-PSGL-1 antibodies and in P-sel -/- -> WT chimeras. The hypercholesterolemia-induced impairment of arteriolar EDR was significantly blunted in mice rendered either neutropenic or thrombocytopenic, and in P-sel -/- -> WT chimeras. Conclusions: The findings indicate that platelet-associated P-selectin contributes to the recruitment of leukocytes and platelets in venules of hypercholesterolemic mice and that the P-selectin-mediated adhesive interactions also contribute to the impaired arteriolar function induced by hypercholesterolemia.