1:Universidad de Cádiz; 2:Instituto de Investigación e Innovación Biomédica de Cádiz; 3:Hospital Universitario Puerta del Mar; 4:University of Southern Denmark

Cell therapy mediated by circulating angiogenic cells (CACs) has been postulated as a promising cardiovascular therapy due to their angiogenic properties, and therefore a good alternative treatment against critical limb ischemia (CLI). However, major efforts are still required to understand their mechanisms of action in order to enhance their regenerative effect. According to previous results of our research group, the incubation ex vivo of CACs with factors secreted by atheroma plaques (AP) promotes activation and mobilization of these cells. For that reason, we aimed to evaluate whether pre-stimulated CACs ex vivo with AP secretomes could potentiate the regenerative properties associated with CACs in vivo, in a murine model of CLI, with a 21 days follow up. The results obtained show an improvement in blood flow and a decrease in the progression of the disease when the CLI mice were treated with CACs, and even more when cells had been previously stimulated with atherosclerotic factors. In addition, our proteomic analysis identified more than 3000 proteins in the ischemic tissue, and the expression patterns in mice treated with CACs stimulated or not with AP factors were totally different. According to functional classifications, altered proteins were associated with different processes such as necrosis, immune response and development of vasculature. In conclusion, atherosclerotic factors cause changes in the regenerative role of CACs.