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Author Spotlight: Modeling an Aspect of Preeclampsia in Female Mice Using Hypoxic Human Placenta-Derived Small Extracellular Vesicles
Published on: January 26, 2024
Small extracellular vesicles-transported lncRNA TDRKH-AS1 derived from AOPPs-treated trophoblasts initiates
Qian Chen1, Jiexing He1, Haihua Liu1
1Department of Obstetrics & Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Insights
Oxidative stress in preeclampsia (PE) involves placenta and endothelial injury. This study identifies TDRKH-AS1 in extracellular vesicles as a key factor, inducing pyroptosis and endothelial dysfunction in PE pathogenesis.
Area of Science:
- Reproductive Biology
- Molecular Medicine
- Cellular Biology
Background:
- Preeclampsia (PE) pathogenesis involves oxidative stress, placental dysfunction, and endothelial injury.
- Circulating factors from oxidative stress-induced placentae trigger systemic inflammation and endothelial dysfunction.
- Advanced oxidation protein products (AOPPs) are novel biomarkers for PE, but underlying mechanisms remain unclear.
Purpose of the Study:
- To investigate the role of placenta-derived extracellular vesicles (pEVs) and specific lncRNAs in PE pathogenesis.
- To identify and characterize lncRNA TDRKH-AS1 as a potential causative factor in PE.
- To elucidate the molecular mechanisms by which sEV-derived TDRKH-AS1 contributes to endothelial dysfunction and PE.
Main Methods:
- Isolation and characterization of small extracellular vesicles (sEVs) from plasma and trophoblast cells using TEM, NTA, and Western blotting.
- Quantification of lncRNA TDRKH-AS1 expression in plasmatic sEVs and placentae via qRT-PCR.
- In vivo studies in pregnant mice and in vitro experiments using HUVECs to assess TDRKH-AS1 function and molecular interactions (RNA pulldown, RIP, ChIRP, Co-IP).
Main Results:
- lncRNA TDRKH-AS1 expression is significantly increased in PE patients' plasmatic sEVs and placentae, correlating positively with disease severity.
- In vivo administration of TDRKH-AS1-enriched sEVs induced PE-like symptoms in pregnant mice, including hypertension and systemic inflammation.
- In vitro, sEV-derived TDRKH-AS1 from AOPPs-treated trophoblasts promoted endothelial pyroptosis by upregulating DDIT4 expression through interaction with PDIA4.
Conclusions:
- lncRNA TDRKH-AS1 within sEVs derived from oxidative stress-affected trophoblasts plays a crucial role in PE pathogenesis.
- TDRKH-AS1 contributes to PE by inducing pyroptosis and exacerbating endothelial dysfunction.
- This study reveals a novel molecular mechanism linking oxidative stress, placental dysfunction, and endothelial injury in preeclampsia.
Background:
Substantial studies have demonstrated that oxidative stress placenta and endothelial injury are considered to inextricably critical events in the pathogenesis of preeclampsia (PE). Systemic inflammatory response and endothelial dysfunction are induced by the circulating factors released from oxidative stress placentae. As a novel biomarker of oxidative stress, advanced oxidation protein products (AOPPs) levels are strongly correlated with PE characteristics. Nevertheless, the molecular mechanism underlying the effect of factors is still largely unknown.
Methods:
With the exponential knowledge on the importance of placenta-derived extracellular vesicles (pEVs), we carried out lncRNA transcriptome profiling on small EVs (sEVs) secreted from AOPPs-treated trophoblast cells and identified upregulated lncRNA TDRKH-AS1 as a potentially causative factor for PE. We isolated and characterized sEVs from plasma and trophoblast cells by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and western blotting. The expression and correlation of lncRNA TDRKH-AS1 were evaluated using qRT-PCR in plasmatic sEVs and placentae from patients. Pregnant mice injected with TDRKH-AS1-riched trophoblast sEVs was performed to detect the TDRKH-AS1 function in vivo. To investigate the potential effect of sEVs-derived TDRKH-AS1 on endothelial function in vitro, transcriptome sequencing, scanning electron Microscopy (SEM), immunofluorescence, ELISA and western blotting were conducted in HUVECs. RNA pulldown, mass spectrometry, RNA immunoprecipitation (RIP), chromatin isolation by RNA purification (ChIRP) and coimmunoprecipitation (Co-IP) were used to reveal the latent mechanism of TDRKH-AS1 on endothelial injury.
Results:
The expression level of TDRKH-AS1 was significantly increased in plasmatic sEVs and placentae from patients, and elevated TDRKH-AS1 in plasmatic sEVs was positively correlated with clinical severity of the patients. Moreover, pregnant mice injected with TDRKH-AS1-riched trophoblast sEVs exhibited a hallmark feature of PE with increased blood pressure and systemic inflammatory responses. Pyroptosis, an inflammatory form of programmed cell death, is involved in the development of PE. Indeed, our in vitro study indicated that sEVs-derived TDRKH-AS1 secreted from AOPPs-induced trophoblast elevated DDIT4 expression levels to trigger inflammatory response of pyroptosis in endothelial cells through interacting with PDIA4.
Conclusions:
Herein, results in the present study supported that TDRKH-AS1 in sEVs isolated from oxidative stress trophoblast may be implicated in the pathogenesis of PE via inducing pyroptosis and aggravating endothelial dysfunction.
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