Treatments employing the matricellular protein thrombospondin-1 (TSP-I) and related compositions are disclosed for stabilizing atherosclerotic plaque and decreasing occurrence of plaque rupture events leading to, for example, myocardial infarction, stroke, and acute limb ischemia. Various peptides, including certain synthetic peptides, related to TSP-I are also disclosed. Such peptides have utility in stabilizing plaque in various contexts, including the disease states mentioned above. Some of these peptides include one or more sequences related to active sites of TSP-I for regulating, e.g., TGF-ss1 and MMP-9 activity. Experimental data show that a representative peptide provides a beneficial effect with systemic injection of the peptide.