Abstract
Apoptosis of endothelial cells (ECs) leads to the development of endothelial dysfunction, which itself is strongly associated with poor cardiovascular prognosis. EC apoptosis can be quantified using flow-cytometry-based enumeration of circulating EC-derived microparticles (EMP) within peripheral blood. Bone marrow-derived endothelial progenitor cells (EPC) contribute to EC regeneration and are an important predictor for cardiovascular mortality. We postulate that EC apoptosis with concomitant release of EMP is an important signal for regenerating cells to initiate EC repair. EMP were generated from human coronary arterial endothelial cells (HCAEC). Proteomic analysis showed that the identified proteins represent cytoskeleton/cytoskeleton-binding proteins, proteins involved in intracellular transport/signalling, and protein folding. In addition, proteins related to apoptosis, proliferation, and migration were identified. HCAEC/EPC were able to incorporate EMP in an annexin I/ phosphatidylserine receptor-dependent way. Incubation of mononuclear cells with EMP lead to an enhanced conversion into early outgrowth EPC. EMP co-incubation also changed the phenotype of cultivated Langerhans-like dendritic cells into an immature phenotype. Co-cultivation of ECs and EPC with EMP prevented TNF-alpha induced cell apoptosis. Migration of EPC was enhanced in response to EMP. Finally, we measured EPC liberation from bone marrow into peripheral blood. Intravenous treatment of C57bl6 mice with EMP enhanced the number of sca-1/flk-1 positive EPC within peripheral blood compared to control. The number of CD31+/Annexin+ EMP and CD34 + /KDR + EPC was determined in 40 patients with coronary artery disease. The number of circulating EMP correlated with EPC function (p<0.001, r=0.601). EMP and EPC seem to substantially interact in an annexin I/PSR dependent way. EMP influence EPC biology in vitro and induces EPC mobilization in vivo. We speculate that the described interaction of EMP with EPC enhance the homing process of EPC within the area of EC damage.
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