TIMP-2-derived 18-mer peptide inhibits endothelial cell proliferation and migration through cAMP/PKA-dependent mechanism

In the present study, we report the regulatory effects and molecular mechanisms of integrin α3β1-binding tissue inhibitor of metalloproteinases-2 (TIMP-2) 18-mer peptide (peptide 9) on proliferation, migration and tubular formation in human umbilical vein endothelial cells. Peptide 9 markedly inhibits vascular endothelial growth factor-A-stimulated cell proliferation. This anti-proliferative activity of peptide 9 is mediated by cAMP/protein kinase A (PKA)-dependent induction of p27Kip1 expression as evidenced by using adenylate cyclase inhibitor SQ22536 or PKA inhibitor H89. Peptide 9-mediated inhibition of endothelial cell migration and tubular formation is also dependent on cAMP/PKA activity. Collectively, our findings clearly show the pharmacological roles and action mechanism of peptide 9 in regulating angiogenic responses through cAMP/PKA activity, and support further development as a potential therapeutics for the treatment of angiogenesis-related disorders including cancer.