Synthesis of sFlt-1 by platelet-monocyte aggregates contributes to the pathogenesis of preeclampsia

Abstract

Soluble fms-like tyrosine kinase (sFlt-1) is an important mediator in the pathogenesis of preeclampsia. We sought to determine whether platelet-monocyte aggregates (PMAs) produced sFlt-1 and whether PMAs contributed to sFlt-1 production in preeclampsia. This was a case-control study of sFlt-1 release from PMAs using blood samples from women with preeclampsia matched by gestational age to pregnant controls. A third group of nonpregnant, reproductive-age women comprised an additional control group. Experiments were also performed using blood from nonpregnant women to elucidate whether inducing PMAs could stimulate sFlt-1 production and, if so, to determine the necessary receptors and pathways. Women with preeclampsia had increased total Flt-1 concentrations in platelets and monocytes at baseline compared with pregnant controls (25 vs 10 pg/mL, P= .0003). sFlt-1 production was elicited from monocytes incubated with thrombin-activated platelets fromnonpregnant women. sFlt-1 production was regulated at the transcriptional level by p38 and nuclear factor-κB-dependent pathways. Activated platelets in preeclampsia bind monocytes to generate sFlt-1. PMAs are a previously unrecognized source of sFlt-1 that may contribute to endothelial dysfunction and systemic inflammation commonly observed in preeclampsia.