title: Endothelial von Willebrand factor recruits platelets to atherosclerosis-prone sites in response to hypercholesterolemia.
abstract: Platelets are thought to play a causal role during atherogenesis. Platelet-endothelial interactions in vivo and their molecular mechanisms under shear are, however, incompletely characterized. Here, an in vivo platelet homing assay was used in hypercholesterolemic rabbits to track platelet adhesion to plaque predilection sites. The role of platelet versus aortic endothelial cell (EC) activation was studied in an ex vivo flow chamber. Pathways of human platelet immobilization were detailed during in vitro perfusion studies. In rabbits, a 0.125% cholesterol diet induced no lesions within 3 months, but fatty streaks were found after 12 months. ECs at segmental arteries of 3- month rabbits expressed more von Willebrand factor (VWF) and recruited 5-fold more platelets than controls (P <.05, n = 5 and 4, respectively). The 3-month ostia had an increased likelihood to recruit platelets compared to control ostia (56% versus 18%, P <.0001, n = 89 and 63, respectively). Ex vivo, the adhesion of 3-month platelets to 3-month aortas was 8.4-fold increased compared to control studies (P <.01, n = 7 and 5, respectively). In vitro, endothelial VWF-platelet glycoprotein (GP) Ib and platelet P-selectin- endothelial P-selectin glycoprotein ligand 1 interactions accounted in combination for 83% of translocation and 90% of adhesion (P <.01, n = 4) of activated human platelets to activated human ECs. Platelet tethering was mainly mediated by platelet GPIb alpha, whereas platelet GPIIb/IIIa contributed 20% to arrest (P <.05). In conclusion, hypercholesterolemia primes platelets for recruitment via VWF, GPIb alpha, and P-selectin to lesion-prone sites, before lesions are detectable.
authors.affiliation: Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.
authors.forename: Gregor
authors.initials: G
authors.lastname: Theilmeier
authors.forename: Carine
authors.initials: C
authors.lastname: Michiels
authors.forename: Erik
authors.initials: E
authors.lastname: Spaepen
authors.forename: Ingrid
authors.initials: I
authors.lastname: Vreys
authors.forename: Désiré
authors.initials: D
authors.lastname: Collen
authors.forename: Jos
authors.initials: J
authors.lastname: Vermylen
authors.forename: Marc F
authors.initials: MF
authors.lastname: Hoylaerts
mesh_terms: D000818:Animals; D001011:Aorta; D001161:Arteriosclerosis / Q000209:etiology / Q000473:pathology*; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D006937:Hypercholesterolemia / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D019007:P-Selectin / Q000378:metabolism / Q000502:physiology; D010973:Platelet Adhesiveness / Q000187:drug effects / Q000502:physiology; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism / Q000502:physiology; D010980:Platelet Membrane Glycoproteins; D011817:Rabbits; D013314:Stress, Mechanical; D014841:von Willebrand Factor / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology
chemical_list: D019007:P-Selectin; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins; C032193:glycoprotein receptor GPIb-IX; D014841:von Willebrand Factor