Background:Resveratrol is a phytoalexin present in red wine. It has been shown to protect LDL from peroxidative degradation. Objective: In consideration of the low plasma concentration of orally adsorbed resveratrol (which is insufficient for antioxidant protection of LDL), we studied another effect of the compound. Design: Because resveratrol is a tyrosine kinase inhibitor like other members of the tyrphostin family, we hypothesized that it has the ability to modify intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule l (VCAM-1) expression by stimulated endothelial cells. We studied the ability of resveratrol to inhibit such adhesion molecule expression and to block the adhesion of monocytes and granulocytes to endothelial cells. Results: We showed that resveratrol, at concentrations as low as 1 mol/L and 100 nmol/L, significantly inhibited ICAM-1 and VCAM-1 expression by tumor necrosis factor ␣ (TNF-␣)-stimulated human umbilical vein endothelial cells and lipopolysaccharide-stimulated human saphenous vein endothelial cells (HSVEC), respectively. In addition, we showed that resveratrol induced a significant inhibition in the adhesion of U937 monocytoid cells to lipopolysaccharide-stimulated HSVEC. Such inhibition was comparable with that obtained when anti-VCAM-1 monoclonal antibody was used instead of resveratrol. Resveratrol also significantly inhibited the adhesion of neutrophils to TNF-␣-stimulated NIH/3T3 ICAM-1-transfected cells, whereas neutrophils activated by formyl-methionyl-leucyl-phenylalanine did not significantly modify adhesion to NIH/3T3 ICAM-1-transfected cells. Conclusions: Our results indicate activity of resveratrol on endothelial cells and a new interpretation of an effect independent of its antioxidant function.

Most studies addressing how cellular phenotypes are affected by the extracellular matrix (ECM) have contrasted cellular responses to different ECM molecules or combinations of molecules, and provided paradigms for interpreting histogenesis, differentiated function, and tissue repair [1][2][3]. We are interested in the possibility that learning whether and how cellular phenotypes are also affected by quantitative changes in the underlying or surrounding ECM may provide paradigms for interpreting pathologies characterized by excess ECM accumulation. One such pathology is diabetic microangiopathy. The process, initiated by the metabolic abnormalities of diabetes, is hallmarked by increased thickness of vascular basement membranes and excess ECM accumulation in the renal mesangium, and leads eventually to microvascular obliteration and the well known clinical sequelae of diabetes [4]. Mesangial expansion is thought to play a pathogenetic role in the loss of glomerular Diabetologia (1997) 40: 879-886 Cytoskeletal changes induced by excess extracellular matrix impair endothelial cell replication m g/ml) of exogenous fibronectin, when compared with HUVEC plated on tissue culture plastic or 0.25, 1.0, and 5.0 m g/ml fibronectin; the decreased replication was attributable to delayed transit through the G 1 phase of the cell cycle. HU-VEC grown on both 1 and 10 m g/ml fibronectin exhibited a modest upregulation of the fibronectinspecific integrin receptor a 5b1, and increased attachment to fibronectin substratum. However, unique to the HUVEC plated on growth-inhibitory concentrations of fibronectin was a redistribution in situ of integrins and vinculin to form more numerous focal adhesions, and an increased polymerization of cytoskeletal actin to form stress fibers. Concentrations (0.01 m g/ ml) of cytochalasin D intended to prevent excess actin polymerization prevented the growth inhibition. Thus, excess ECM hampers endothelial cell replication in vitro through increased cell-ECM adhesion and attendant cytoskeletal rearrangements. These phenotypic changes provide probes to test whether cell-ECM interactions are altered in diabetic vessels in a direction that may compromise orderly endothelial cell renewal and its antithrombogenic function. [Diabetologia (1997)

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