Proatherogenic flow conditions initiate endothelial apoptosis via thrombospondin-1 and the integrin-associated protein

Recently it has been shown that vascular endothelial cells (EC) are complet ely devoid of apoptosis if cultivated under a steady laminar flow and that apoptosis is induced by turning off the flow. An autocrine loop of thrombos pondin-1 (TSP-1) and the alpha (v)beta (3) integrin/integrin-associated pro tein (IAP) complex has been identified as the molecular coupling device bet ween flow and apoptosis. Lack of blood flow is a rare and mostly transient phenomenon whereas irregular flow conditions are permanently present at art erial bifurcations and sites of abnormal vessel morphology. Irregular flow conditions are established here either by the action of a cone-and-plate ty pe flow apparatus generating a uniform turbulent flow or in a flow chamber by insertion of a local hindrance creating a zone of unsteady laminar flow with vortex formation and lowered shear stress. In both cases apoptosis is induced either throughout the entire monolayer or restricted to the locally defined area. Flow disturbance and apoptosis are coupled by the described autocrine loop of TSP-1 and the integrin/LAP receptor complex. In vivo athe rosclerotic lesions occur predominantly at sites of flow irregularities, wh ich are thought to be pro-atherogenic. Thus we propose a key role of the id entified mechanosensitive apoptosis induction for the initiation of atheros clerosis. (C) 2001 Academic Press.