Elastin breakdown in the walls of uterine spiral arteries during early pregnancy facilitates their transformation into dilated, high-flow, low-resistance channels. Elastin-derived peptides (EDP) can influence cell migration, invasion and protease activity, and so we hypothesized that EDP released during elastolysis promote extravillous trophoblast (EVT) invasion and further elastin breakdown. Treatment of the trophoblast cell line SGHPL4 with the elastin-derived matrikine VGVAPG (1 μg/ml) significantly increased total elastase activity, promoted migration in a wound healing assay and increased invasion through Matrigel-coated transwells compared with vehicle control (0.1% DMSO) or the scrambled sequence VVGPGA. Furthermore, treatment of first-trimester placental villous explants with this EDP significantly increased both the area of trophoblast outgrowth and distance of migration away from the villous tips. Primary first-trimester cytotrophoblast exposed to VGVAPG (1 μg/ml) for 30 min showed increased phosphorylation of endothelial nitric oxide synthase and activation of the mitogen activated protein kinase pathway, events also associated with tumour cell migration and invasion. These in vitro observations suggest liberation of bioactive EDP during induction of elastolysis in the uterine spiral arteries may orchestrate a positive feedback loop that promotes EVT invasion and further elastin breakdown, contributing to the process of vascular remodelling.