In the present study we (i) determine the importance of AMI-induced C5a elevation on mechanical changes to the endothelial cell surface using the atomic force microscopy (AFM)-based nanoindentation technique, (ii) evaluate the contribution of C5a to endothelial dysfunction and the condition of the eGC and to leukocyte-endothelium interaction, and (iii) investigate the effect of administering the C5a-Receptor-1 antagonist “PMX53” on restoring vascular nanomechanics and endothelial function. Here, C5 is linked to endothelial dysfunction.