We sought to develop bioactive hydrogels to facilitate arterial healing, e.g., after balloon angioplasty. Toward this end, we developed a new class of proteolytically sensitive, biol. active polyethylene glycol (PEG)-peptide hydrogels that can be formed in situ to temporarily protect the arterial injury from blood contact. Furthermore, we incorporated endothelial cell-specific biol. signals with the goal of enhancing arterial reendothelialization. Here we demonstrated efficient endothelial cell anchorage and activation on PEG hydrogel matrixes modified by conjugation with both the cell adhesive peptide motif RGD and an engineered variant of vascular endothelial growth factor (VEGF). By crosslinking peptide sequences for cleavage by MMP-2 into the polymer backbone, the hydrogels became sensitive to proteolytic degrdn. by cell-derived matrix metalloproteinases (MMPs). Anal. of mol. hall-marks assocd. with endothelial cell activation by VEGF-RGD hydrogel matrixes revealed a 70% increase in prodn. of the latent MMP-2 zymogen compared with PEG-peptide hydrogels lacking VEGF. By addnl. provision of transforming growth factor b1 (TGF-b1) within the PEG-peptide hydrogel, conversion of the latent MMP zymogen into its active form was demonstrated. As a result of MMP-2 activation, strongly enhanced hydrogel degrdn. by activated endothelial cells was obsd. Our data illustrated the crit. importance of growth factor activities for remodeling of synthetic biomaterials into native tissue, as it is desired in many applications of regenerative medicine. Functionalized PEG-peptide hydrogels could help restore the native vessel wall and improve the performance of angioplasty procedures. [on SciFinder (R)]