Overexpression of circulating soluble fms-tyrosine kinase 1 (sFlt1) is associated with PE and thought to play a causative role in its symptoms and postpartum risk factors. The mechanism(s) of regulation of sFlt1 has not been determined. Our objective in this study was to determine whether there are differences in the regulation by cAMP of placental sFlt1 expression in PE versus normal pregnancies. We isolated decidual stromal cells (DSC) and villous explants (VE) from delivered placenta of women with PE (n=8) and normal pregnancies (n=6). Explants were treated with 0.5 mM dibutyryl cAMP (cAMP) for 72 hours, and the DSC were treated for 8 days. Quantitative real-time RT-PCR was performed to estimate sFlt1 mRNA levels, with hRPL-17 serving as a housekeeping control gene. Data is presented as mean-fold changes of sFlt1 mRNA in the presence of cAMP (± standard deviation) compared with untreated cultures using GraphPad Prism. A p value of <0.05 was considered significant. Primary DSC from both normal and PE placentas treated with cAMP showed a significant down-regulation of sFlt1 expression compared with untreated cells (0.34 ±0.25-fold and 0.36 ±0.22-fold, respectively; p=0.0003). VE obtained from normal pregnant women also showed a down-regulation of sFlt1 expression in response to cAMP (0.56 ±0.2 fold). However, the VE from PE placenta showed an upregulation of sFlt1 (1.82 ±0.8 fold, p=0.0001). While cAMP-mediated regulation of sFlt1 is similar in the decidua of normal vs PE placentas, there are marked differences in this regulation in the villous cells from these 2 groups of patients. The increased expression of sFlt1 induced by cAMP in VE from PE patients suggests that placentas of women with PE may have alterations in cAMP-mediated regulation of this gene, leading to an overexpression and secretion of sFlt1.