Interactions between vascular smooth muscle cells (SMCs) and macrophages (M<)>s) are critical to the development of atherosclerosis. We have previously demonstrated that y-linolenic acid (GLA)-enriched dietary oils enhance the ability of M<|>s to downregulate vascular SMC DNA synthesis in a cyclooxygenase-dependent fashion (Arterio. Thromb. Vase. Biol. 15:1397;1995). The present study was designed to identify the soluble factors critical in this response. Mice were fed one of 4 diets containing either 10% (w/w) com oil (CO), safflower oil ethyl ester (SAP), GLA-enriched triglycride (GLA-TG), or a mix (65:35, w/w) of SAP and purified GLA free fatty acid (GLA-FFA) for 2 wk. Resident peritoneal M$s were seeded in an upper cell culture chamber separated by a semi-permeable membrane with a 30 kDa cutoff. Various concentrations of anti-prostaglandin E] (PGEi), anti-PGD2, antiplatelet-derived growth factor, and denatured anti-PGEj were added to the Ms (upper chamber) immediately before co-culture with naive chow-fed vascular SMCs (lower chamber) in the presence of exogenous PGEi (0.1-10 M) or vehicle for 96 h. Following the incubation, SMCs were trypsinized and counted. SMC proliferation was significantly (P<0.05) decreased in GLA-TG and GLA-FFA groups compared to CO and SAP. The effect of GLA was only blocked by anti-PGEi in a concentration-dependent manner. Exogenous PGEi reinstated the anti-proliferative effect of GLA on SMCs in a concentiationdependent fashion. These data indicate that dietary GLA enhances M(f>-derived PGE ], a critical anti-proliferative soluble factor, which may favorably modulate the atherogenic process. (Supported by the TAMU REP program and Scotia Pharmaceuticals.).