RhoB/ROCK mediates oxygen–glucose deprivation-stimulated syncytiotrophoblast microparticle shedding in preeclampsia

Abstract

Increased circulating syncytiotrophoblast microparticles (STBMs) are often associated with preeclampsia (PE) but the molecular mechanisms regulating STBM shedding remain elusive. Experimental evidence has shown that actin plays a key role in STBM shedding and that Rho/ROCK is important in regulating actin rearrangement. To investigate the role of RhoB/ROCK-regulated actin arrangement in STBM shedding in PE, chorionic villous explants were prepared from placenta of patients with normotensive or PE pregnancies and BeWo cells were fused to imitate syncytiotrophoblasts. The oxygen-glucose deprivation (OGD) conditions were applied to imitate the pathophysiology of PE in vitro. The results showed that RhoB and ROCK were activated in the preeclamptic placenta, accompanied by increased actin polymerization and decreased outgrowing microvilli. In villous tissue cultures or BeWo cells, OGD activated RhoB, ROCK1 and ROCK2 and promoted STBM shedding and actin stress fibers formation. In BeWo cells, RhoB overexpression activated ROCK1 and ROCK2, leading to F-actin redistribution and STBM shedding and the OGD-induced actin polymerization and STBM shedding could be reversed by RhoB or ROCK knockdown. These results reveal that RhoB and ROCK play a key role in PE by targeting STBM shedding through actin rearrangement and that RhoB/ROCK intervention may be a potential therapeutic strategy for PE.

Syncytiotrophoblast-Derived Extracellular Vesicles in Pathophysiology of Preeclampsia

“…SDEVs are alternatively called placental syncytiotrophoblast microvillous membrane (Cockell et al, 1997; Aly et al, 2004), syncytiotrophoblast microparticles (Han et al, 2016) and placental-derived microvesicles (Holder et al, 2012). Similar to EVs of other cells, SDEVs are highly heterogeneous in their morphology, carried cargos, biological properties, and activities toward target cells.…”

“…Together, these pathological activities induced by SDEVs are significantly exaggerated in PE to restrict fetal growth and result in recurrent miscarriage (Lok et al, 2011; Baig et al, 2013). Han et al (2016) recently reported that the RhoB/ROCK-regulated actin arrangement promotes the shedding of SDEVs from syncytiotrophoblasts in PE patients, indicating that regulating RhoB/ROCK signaling may be a new therapeutic strategy for patients with PE.…”

Syncytiotrophoblast Derived Extracellular Vesicles in Relation to Preeclampsia

“…38 Upregulation of RhoB/ROCK, regulators of actin rearrangement, increased STBEV release in vitro; moreover RhoB/ROCK knockdown reduced STBEV release in a hypoxic model of PE. 39 Vitamin D supplementation has been shown to reduce ROCK1 activation in trophoblast cultures, which could contribute to the clinically preventative effect of vitamin D supplementation in PE. 40 Substantially more work is needed to confirm this theory.…”

Upregulation of RND3 Affects Trophoblast Proliferation, Apoptosis, and Migration at the Maternal-Fetal Interface

“…The ROCK1 activity was evaluated by immunoprecipitating ROCK1 and then performing an in vitro kinase activity assay (Mong and Wang, 2009;Han et al, 2016). Cells were lysed using a lysis buffer and then incubated for 1 h at 4 • C with 2 µg of isotype control IgG, rabbit anti-ROCK1.…”