LMWH prevents platelet and extracellular vesicle mediated thrombo-inflammation

Objective Low molecular weight heparins (LMWH) are the most commonly used therapeutics for thromboembolic events during pregnancy. However their role in PE remains controversial, but studies suggest an overall protective effect. . It has been proposed that although LMWHs have potent anti-coagulant functions, they may convey their beneficial effects independent of their anti-coagulant activity. We have recently shown that EVs and platelets promote trophoblast inflammasome activation in PE. We therefore hypothesized that LMWH convey anti-inflammatory effects in PE by preventing NLRP3 inflammasome activation in trophoblast cells.

Material and Methods Procoagulant EVs were injected into C57/Bl6 pregnant mice. LWMH was injected s.c. 30 minutes before EV injections and embryonic survival and growth restriction (IUGR) was studied. Trophoblast differentiation and trophoblast proliferation was studied using qRT-PCR and Ki-67 staining respectively. Inflammasome markers NLRP3 and IL-1β were evaluated using immunoblotting. Differentiated mouse trophoblast stem cells were treated with EVs and LWMH to study the protective effect of LWMH on inflammasome activation and proliferation. Analysis of human PE placentae explants treated with LMWH and trophoblast cells established translational relevance.

Results LMWH rescues the EV-injected pregnant mice from embryonic death and IUGR. LWMH prevented EV induced trophoblast inflammasome activation, restored altered trophoblast differentiation and improved proliferation in vivo and in vitro. Mechanistically, LWMH was able to activate HB-EGF signaling pathway resulting in PI3-Kinase-Akt signaling in trophoblast cells in order to prevent inflammasome activation. In human PE placental explants, inflammasome activation and PI3-Kinase-Akt signaling events were restored upon treatment with LMWH.

Conclusion These results establish a protective effect of LMWH in preventing EV induced inflammasome activation and reduced trophoblast function, which contributes to the placental defect and embryonic demise in PE. These effects are mediated by HB-EGF-PI3-Kinase-Akt signaling axis. LWMH is a safe therapy in placental defects associated with excess platelet activation and placental inflammasome activation, as observed in PE.

Publikationsverlauf

Artikel online veröffentlicht:
18. Juni 2021