Objectives Preeclampsia is a hypertensive disorder of pregnancy with no available medical treatment. We recently reported sulfasalazine, an anti-inflammatory medication, to be a candidate therapeutic for preeclampsia. We showed sulfasalazine decreases placental secretion of soluble Fms-like tyrosine kinase-1 (sFlt-1), an anti-angiogenic factor strongly implicated in the pathogenesis of preeclampsia. However, the cellular mechanism(s) by which sulfasalazine reduces placental sFlt-1 are yet to be determined. Recently we also reported that both the mitochondria and the epidermal growth factor receptor (EGFR) signalling pathways regulate secretion of placental sFlt-1. In this study we sought to assess directly whether sulfasalazine's capacity to reduce sFlt-1 secretion may be mediated via EGFR or the mitochondria. Methods and results Using primary cytotrophoblast cells, we confirmed sulfasalazine reduced sFlt-1 secretion. Interestingly, when we measured the mRNA expression of EGFR, we found a reduction in EGFR expression which closely mirrored the changes in sFlt-1 secretion. At the protein level, sulfasalazine significantly reduced phosphorylated and active EGFR (phosphorylated/total) expression. Additionally, sulfasalazine significantly reduced the protein expression of ERK1/2 and STAT3 which are key adaptor molecules downstream of EGFR. Next, we assessed mitochondrial respiration following sulfasalazine treatment and found no effect on basal respiration, ATP production, proton leak or maximal respiration. Conclusion Sulfasalazine reduces EGFR and down-stream signalling molecule expression coincident with reduced sFlt-1 secretion. EGFR signalling is a potential mechanism by which sulfasalazine decreases placental secretion of sFlt-1. Further interrogation of the EGFR may identify new candidate treatments for preeclampsia.
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