LMWH prevents thrombo-inflammation in the placenta via HBEGF-AKT signalling.

ABSTRACT

Low molecular weight heparins (LMWH) are used to prevent or treat thromboembolic events during pregnancy. While studies suggest an overall protective effect of LMWH in preeclampsia (PE), their use in preeclampsia remains controversial. LMWH may convey beneficial effects in preeclampsia independent of their anti-coagulant activity, possibly by inhibiting inflammation. Here we evaluated whether LMWH inhibit placental thrombo-inflammation and trophoblast NLRP3 inflammasome activation. Using an established procoagulant extracellular vesicle (EV)-induced and platelet-dependent preeclampsia-like mouse model, we show that LMWH reduces pregnancy loss and trophoblast inflammasome activation, restores altered trophoblast differentiation and improves trophoblast proliferation in-vivo and in-vitro. Moreover, LMWH inhibits platelet independent trophoblast NLRP3 inflammasome activation. Mechanistically, LWMH activates via Heparin binding epidermal growth factor (HBEGF) signaling the PI3-Kinase-AKT pathway in trophoblasts thus preventing inflammasome activation. In human preeclampsia placental explants, inflammasome activation and PI3-Kinase-AKT signaling events were reduced with LMWH treatment compared to those without LMWH treatment. Thus, LMWH inhibits sterile inflammation via the HBEGF signaling pathway in trophoblasts and ameliorates preeclampsia-associated complications. These findings suggest that drugs targeting the inflammasome may be evaluated in preeclampsia and identify a signaling mechanism through which LMWH ameliorates preeclampsia, thus providing a rationale for the use of LMWH in preeclampsia.