Homocysteine enhances neutrophil-endothelial interactions in both culturedhuman cells and rats in vivo

Despite intense investigation, mechanisms linking the development of occlus ive vascular disease with elevated levels of homocysteine (HCY) are still u nclear. The vascular endothelium plays a key role in regulating thrombogene sis and thrombolysis, We hypothesized that vascular lesions in individuals with elevated plasma HCY may be related to a dysfunction of the endothelium triggered by HCY, We investigated the effect of HCY on human neutrophil ad hesion to and migration through endothelial monolayers. We also examined th e effect of HCY on leukocyte adhesion and migration in mesenteric venules o f anesthetized rats. We found that pathophysiological concentrations of HCY in vitro induce increased adhesion between neutrophils and endothelial cel ls. This contact results in neutrophil migration across the endothelial lay er, with concurrent damage and detachment of endothelial cells. In vivo, HC Y infused in anesthetized rats caused parallel effects, increasing leukocyt e adhesion to and extravasation from mesenteric venules. Our results sugges t that extracellular H2O2, generated by adherent neutrophils and/or endothe lial cells, is involved in the in vitro endothelial cell damage. The possib ility exists that leukocyte-mediated changes in endothelial integrity and f unction may lead to the vascular disease seen in individuals with elevated plasma HCY.