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Microparticles released by senescent endothelial cells promote premature endothelial senescence associated with an impaired NO formation and oxidative stress

Circulating levels of endothelial microparticles (EMPs) are elevated in vascular diseases such as coronary artery disease, peripheral vascular disease or rejection after heart transplantation. EMPs, besides being relevant biomarkers, might also contribute to the development of endothelial dysfunction and vascular damage. This study examined whether the induction of endothelial senescence is associated with EMPs shedding, and if senescence-related EMPs promote endothelial senescence and prothrombotic changes of the endothelial cell. Replicative senescence was induced by serial passaging of primary cultures of porcine coronary artery endothelial cells (ECs) up to the third passage (P3). Cells retained normal phenotype of ECs at P1 and P2 whereas at P3 an increased proportion exhibited features of senescence with cell cycle arrest in the G0/G1 phase and senescence-associated β-galactosidase (SA-β-gal) activity. In addition, senescence was associated with increased EMP shedding and no detectable apoptosis. Exposure of ECs at P1 to EMPs collected from the conditioned medium of ECs at P3 induced cell cycle arrest and increased SA-β-Gal activity in target cells. Furthermore, EMPs isolated from ECs at P3 increased cellular oxidative stress and the expression of the senescence markers p53 and its downstream targets p21 and p16. Moreover, EMPs reduced the ability of ECs to inhibit platelet aggregation and up-regulated TF expression and activity at EC cell membrane. The present findings indicate that endothelial senescence favors the increased shedding of EMPs, which, in turn, promote premature senescence and an endothelial prothrombotic phenotype. The response to senescence-related EMPs involves oxidative stress, the up-regulation of p53 and p21, and a reduced formation of nitric oxide and up-regulation of TF. Our data further suggest that EMPs released by senescent endothelial cells may contribute to the development of an endothelial dysfunction and thrombogenicity. In spite of the progresses of the imagers' efficiency (which used for biomedical diagnosis in order to detect pathogens and specific cellular, tissular and molecular targets), notably X-ray and optical modality, their use and potentials are still dramatically limited by the low efficiency and toxicity of contrast agents. 1 This study presents the development of new contrast agents overcoming these limitations, based on non-toxic nano-emulsions highly loaded in contrasting materials, intended to fluorescence tomography and/or computed tomography (CT) preclinical imaging. The success of the formulation of such contrast agents relies on several interdependent challenges: (i) Designing efficient and cost-effective contrast that are easy to synthesize and that can be loaded at high concentrations in nanoparticles. (ii) Developing …