EGFR (Epidermal Growth Factor Receptor) Signaling and the Mitochondria Regulate sFlt-1 (Soluble FMS-Like Tyrosine Kinase-1) Secretion

Abstract

Preeclampsia is a hypertensive disorder of pregnancy characterized by maternal endothelial dysfunction and end-organ damage. The antiangiogenic factor, sFlt-1 (soluble FMS-like tyrosine kinase-1) has been strongly implicated in the pathogenesis of preeclampsia. sFlt-1 is secreted into the maternal circulation where it antagonizes VEGF (vascular endothelial growth factor) and ultimately disrupts vascular homeostasis. However, the upstream mechanisms regulating release of sFlt-1 are poorly characterized. We investigated the roles of key prosurvival pathways, EGFR (epidermal growth factor receptor) signaling, and the mitochondria, in regulating sFlt-1 production. We initially found that the mRNA and protein of EGFR and downstream adaptor molecules were significantly increased in preeclamptic placental tissue relative to normotensive controls. Inhibiting the EGFR signaling cascade using siRNA (small interfering ribonucleic acid) or small molecule inhibitors significantly reduced sFlt-1 release from primary cytotrophoblast (placental cells). Additionally, inhibiting the mitochondrial electron transport chain or activating downstream energy-sensing molecules (AMPK [AMP-activated kinase], SIRT1 [sirtuin 1 ], and PGC1α [PPAR-γ co-activator 1]) also significantly reduced sFlt-1 secretion from cytotrophoblast cells, without affecting EGFR signaling. In vivo, treating pregnant mice with gefitinib (an EGFR inhibitor) or resveratrol (perturbs mitochondrial function) significantly reduced circulating murine sFlt-1 compared with vehicle control. Furthermore, treating primary cytotrophoblasts with therapeutics which have been previously found to reduce sFlt-1 secretion, either reduced EGFR signaling (esomeprazole and statins) or perturbed mitochondrial function (esomeprazole, resveratrol, and metformin). Additionally, targeting both pathways simultaneously produced additive reductions in sFlt-1 secretion. Thus, we have identified 2 key survival pathways that seem to be overactive in preeclampsia and involved in the regulation of placental sFlt-1 secretion.

miR‑342‑3p suppresses cell migration and invasion in preeclampsia by targeting platelet‑derived growth factor receptor α

“…The present study aimed to determine the mechanism underlying incomplete trophoblastic invasion in PE. However, endothelial dysfunction is also one of the major causes of PE (4), yet this was not explored in our study this paper; thus, this should be investigated in the future.…”

“…The pathogenesis of PE is not fully understood; thus, as an effective treatment for PE, pregnancies may be terminated. At present, PE is considered to be associated with dysfunction of the placenta (3), endothelial dysfunction (4) and abnormal increases in the apoptosis of trophoblasts (5). Of note, increased migration and invasion of trophoblastic cells, and decreased apoptosis have been hypothesized as potential therapeutic strategies for the treatment of PE; however, further investigation is required.…”

Deep Sequencing Identified Dysregulated Circulating MicroRNAs in Late Onset Preeclampsia

“…Furthermore, insulin resistance and endothelial dysfunction represent early events in individuals at high risk of developing cardiovascular disease later in life (35). The Epidermal Growth Factor Receptor (EGFR) signaling, which is related to fetal growth restriction, gestational trophoblastic diseases and PE was found significantly enriched in the present study (36). Hastie et al (2019) showed simultaneous targeting of both EGFR signaling and mitochondrial function using a combination of esomeprazole and metformin results in additive reductions in sFlt-1 production suggesting their use as preventive therapeutic interventions for PE (36).…”

Exploring the Mechanism of Action of Banxia Baizhu Tianma Decoction against Preeclampsia by a Network Pharmacology Approach

“…AKT acts on a variety of targets involved in many cellular processes, such as metabolism, cell cycle, survival, and differentiation [50][51][52]. It has been demonstrated that placental pathology in preeclampsia and retarded fetuses is related to changes in the expression pattern of EGFR [53], and the antiangiogenic factor, sFlt-1 (soluble FMS-like tyrosine kinase-1), has been strongly implicated in the pathogenesis of preeclampsia and was mediated by EGFR signaling [54].…”