Angiogenesis plays an important role in a wide range of physiological processes. In this paper, we designed and synthesized a series of new analogs including 11 line-peptides and 9 cyclo-peptides by using a marine cyclopeptide (compound 21) which could stimulate angiogenesis on zebrafish in our previous studies as lead compound. The majority of compounds synthesized exhibited angiogenic effects when tested in vivo on zebrafish. Among them, compounds 3, 4, 10, and 15 exhibited much stronger angiogenic activities on zebrafish compared with the lead compound, and the line peptides 3 and 4 showed the most significant angiogenic activities. The SAR (structure-activity relationship) analysis revealed that Val, Lys and Ala are important for the activity. Further studies showed that 3 could concentration-dependently stimulate proliferation, migration and invasion in HUVECs (human umbilical vein endothelial cells) in vitro. To explore the angiogenesis mechanism of this series of compounds, a microarray analysis was carried out to study the gene expression profile and the result showed that 26 genes were upregulated more than 2 fold changes in treatment with 3 on zebrafish, in which mmp9 and mmp13a, two angiogenesis-related genes, increased up to 5-folds. Moreover, through the GO (gene ontology) enrichment analysis, mmp9 and mmp13a genes are the central nodes in the biological processes network. These results suggested that the pro-angiogenic mechanism of this kind of small molecular peptides is related with the expression and regulation of mmp genes in the signal transduction pathways. Additionally, one mmp inhibitor was chosen for further confirmation.