Antiangiogenic activity can be elicited by the kringle domains I and 2 of tissue-type plasminogen activator(TK1-2), or the kringle 2 domain alone In a previous report, we showed that the anti-migratory effect of TK1-2 is mediated in part by its interference with integrin alpha 2 beta 1 Since integrin alpha 2 beta 1 interacts with collagen type I through the DGEA (Asp-Gly-Glu-Ala) amino acid sequence, and a similar sequence, DGDA (Asp-Gly-Asp-Ala), exists in the kringle 2 domain, we investigated whether the DGDA sequence has a role in antiangiogenic activity of TK1-2. In an adhesion assay, the DGDA peptide inhibited adhesion of human umbilical vein endothelial cells (HUVECs) to immobilized TK1-2 Pretreatment of the DGDA peptide also blocked anti-migratory activity of TK1-2. When the DGDA peptide alone was tested for antiangiogenic activity. it effectively inhibited VEGF-induced migration of HUVECs and tube formation on Matrigel. In addition, the DGDA peptide decreased differentiation of endothelial progenitor cells on collagen type I matrix. These data suggest that the DGDA sequence presents a functional epitope of TK1-2 and that it can be used as a potential novel antiangiogenic peptide. (c) 2009 Elsevier Inc. All rights reserved