PURPOSE.: Systemic sclerosis (SSc) is a autoimmune disease marked by aberrant activation and apoptosis of endothelial cells (ECs) and decreased numbers circulating angiogenic cells (CACs). The aim of the present study was to analyze whether microparticles might link pathologic activation and apoptosis of ECs with the reduced numbers of CACs. METHODS.: Apoptosis was quantified by staining for annexin V and measurement of the caspase 3 activity. The uptake of microparticles by CACs was determined by FACS and by fluorescence microscopy. Tritiated arachidonic acid and PtdIns3,5BP were used to demonstrated the transfer of arachidonic acid and highlight the role of the acid sphingomyelinase in microparticles induced apoptosis of EPCs. RESULTS.: Microparticles derived from activated or apoptotic ECs, which are strongly increased in the blood of SSc patients, induce apoptosis in CACs in a dose-dependent manner. Microparticles, which are rich in arachidonic acid, are phagocytosed by CACs. Inhibition of phagocytosis prevents the induction of apoptosis in CACs by microparticles. Microparticles can transport arachidonic acid from ECs to CACs and purified arachidonic acid mimics the pro-apoptotic effects of microparticles. Arachidonic acid activates the acid sphingomyelinase and inhibition of acid sphingomyelinase prevents microparticle induced apoptosis of CACs. Thus, phagocytosis of microparticles might stimulate the activity of acid sphingomyelinase and activate the apoptotic machinery. CONCLUSION.: The induction of apoptosis in CACs by microparticles derived from ECs provides a novel link between aberrant activation or apoptosis of ECs, decreased numbers of CACs and impaired formation of new vessels in SSc.