Summary
The pathogenesis of atherosclerosis involves the interplay of haematopoietic, stromal
and endothelial cells. Platelet interactions with endothelium and leukocytes are pivotal
for atherosclerosis promotion. Glycoprotein (GP) Ibα is the ligand-binding subunit
of the platelet GPIb-IX-V receptor complex; its deficiency causes the Bernard-Soulier
syndrome (BSS), characterised by absent platelet GPIb-IX-V, macrothrombocytopenia
and bleeding. We designed this study to determine the role of platelet GPIbα in the
pathogenesis of atherosclerosis using two unique knockout models. Ldlr-/-
mice were reconstituted with wild-type (wt), GPIbα-/- (lacks GPIbα) or chimeric IL-4R/GPIbα-Tg (lacks GPIbα extracellular domain) bone marrow and assayed for atherosclerosis development
after feeding with pro-atherogenic “western diet”. Here, we report that Ldlr-/-
mice reconstituted with GPIbα-/-
bone marrow developed less atherosclerosis compared to wt controls; accompanied by
augmented accumulation of pro-inflammatory CD11b+ and CD11c+ myeloid cells, reduced
oxLDL uptake and decreased TNF and IL 12p35 gene expression in the aortas. Flow cytometry
and live cell imaging in whole blood-perfused microfluidic chambers revealed reduced
platelet-monocyte aggregates in GPIbα-/-
mice, which resulted in decreased monocyte activation. Interestingly, Ldlr
-/- mice reconstituted with IL-4R/GPIbα-Tg bone marrow, producing less abnormal platelets, showed atherosclerotic lesions similar
to wt mice. Platelet interaction with blood monocytes and accumulation of myeloid
cells in the aortas were also essentially unaltered. Moreover, only complete GPIbα
ablation altered platelet microparticles and CCL5 chemokine production. Thus, atherosclerosis
reduction in mice lacking GPIbα may not result from the defective GPIbα-ligand binding,
but more likely is a consequence of functional defects of GPIbα-/-
platelets and reduced blood platelet counts.
Keywords
Aorta - atherosclerosis - inflammation - myeloid cells - platelets