Abstract 58: Delayed Atherosclerosis in a Mouse Model of Bernard-Soulier Syndrome is Independent of Glycoprotein Ibα Extracytoplasmic Domain Deficiency

Abstract

The pathogenesis of atherosclerosis involves the interplay of blood, stromal and endothelial cells; platelet interactions with vascular endothelium and leukocytes promote atherosclerosis. Glycoprotein (GP) Iba is the ligand-binding subunit of the platelet GPIb-IX-V adhesion receptor complex; its deficiency causes the Bernard-Soulier syndrome (BSS), characterized by absent platelet GPIb-IX-V, macrothrombocytopenia and bleeding. We found that Ldlr-/- mice reconstituted with GPIb a -/- as compared to wild type control developed delayed atherosclerosis associated with reduced platelet binding to blood myeloid cells and reduced accumulation of CD11b + and CD11c + myeloid cells in the aortas. Live imaging in whole blood-perfused microfluidic chambers revealed reduced platelet-monocyte aggregates in GPIb a -/- mice, which also showed decreased TNF in blood monocytes along with decreased TNF and IL12p35, but enhanced arginase1 in aortas. In contrast, Ldlr-/- mice reconstituted with chimeric IL-4R/ GPIb a-Tg bone marrow produce platelets expressing GPIb-IX-V without the GPIba extracytoplasmic domain but less abnormal with respect to size and count and showed atherosclerotic lesion sizes similar to control mice. In conclusion, reduced platelet interactions with myeloid cells and delayed onset of atherosclerosis are not caused by defective GPIba-ligand binding but may result from the low platelet count and, possibly, other functional defects of BSS platelets.