Intimal deposition of functional von Willebrand factor in atherogenesis

During the formation of intimal thickening in normocholesterolemic rabbits, von Willebrand factor (vWF) is increased in the endothelial cells (ECs) an d deposited in the intima. We investigated whether this also occurs during cholesterol-induced plaque formation, whether the synthesis of vWF increase s, and whether this influences platelet adhesion. Rabbits were fed a choles terol-rich (0.3%) diet for 26 weeks. Thereafter, half of the animals receiv ed a normal diet for another 26 weeks (cholesterol withdrawal). To induce i ntimal thickening in normocholesterolemic rabbits, collars were positioned around the carotid artery. Arterial segments were studied using immunohisto chemistry, reverse transcription-polymerase chain reaction, electron micros copy, and platelet adhesion tests. Cholesterol treatment induced plaque for mation in the aorta. The ECs had a cuboidal aspect, showed a dense immunore activity for vWF, a pronounced rough endoplasmic reticulum, and numerous We ibel-Palade bodies. There were subendothelial vWF deposits in the plaques a nd vWF mRNA was significantly increased as compared with controls. Similar changes were seen after collar-induced intimal thickening. After cholestero l withdrawal, both vWF mRNA and the ultrastructural morphology of the ECs n ormalized, and the vWF deposits disappeared From the plaque. Perfusion stud ies with anticoagulated rabbit blood over cross-sections of atherosclerotic aortas revealed increased vWF-mediated platelet adhesion in the subendothe lial plaque region. Whereas rabbit platelets perfused through the lumen adh ered to the same extent to de-endothelialized aortas of normocholesterolemi c and atherosclerotic rabbits, vWF mediated platelet adhesion to endotheliu m was observed in atherosclerotic but not in normal aortas. Our results sho w an increased synthesis and (sub)endothelial presence of vWF after vascula r injury, with functional consequences for platelet deposition on the vesse l wall.