Abstract Porcine aortic endothelial cells (PAECs) in culture constitutivery secrete polypeptide (endothelium-derived) growth factors (EDGFs) into the surrounding medium. Incubation of PAECs with human peripheral blood polymorphonuclear leukocytes (PMNs) caused a significant increase in EDGF release as assessed by pH]thymidine incorporation into BALB/c 3T3 mouse fibroblasts and cell proliferation assay. The effect was time dependent and correlated with the number of PMNs, reaching a maximum with a 1:1 PAEC to PMN ratio. Generation of mitogenic activity was prevented by cycloheximide, indicating a requirement for de novo protein synthesis. Antibody-mediated inhibition assays suggested that mitogenic activity was due to platelet-derived growth factor and basic fibroblast growth factor. When supernatant from N-formyl-methionyl-leucyl-phenylalanine-stimulated PMNs was substituted for PMNs during incubation with PAECs, powerful mitogenic activity was generated, indicating the involvement of soluble mediators. A role for free oxygen radicals was ruled out by experiments in which superoxide dismutase and catalase did not prevent the increase in mitogenic activity. By contrast, serine protease inhibitors such as soybean trypsin inhibitor, aantitrypsin, and eglin C reduced the PMN-stimulating activity by 70%, 80%, and 100%, respectively. The possible involvement of cathepsin G and elastase was investigated. Cathepsin G and elastase, when substituted for PMNs, increased the release of EDGFs in a dose-dependent fashion, mimicking the effect of PMNs. These findings suggest a new role for leukocyte-vessel wall interactions in the proliferative feature of atherosclerosis.