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ToolsLv, Zi, Xiong, Li-ling, Qin, Xian, Zhang, Hua, Luo, Xin, Peng, Wei, Kilby, Mark D., Saffery, Richard, Baker, Philip N. and Qi, Hong-bo (2021) Role of GRK2 in trophoblast necroptosis and spiral artery remodeling: Implications for preeclampsia pathogenesis. Frontiers in Cell and Developmental Biology, 9. ISSN 2296-634X
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Abstract
Impaired invasion of extravillous trophoblasts and severe oxidative stress manifest the poor placentation in preeclampsia, which is life-threatening and more than a hypertensive disease of pregnancy. Previous studies have reported that G protein-coupled receptor kinases (GRKs) play a key role in initiating hypertension and hypertensive renal damage, yet little evidence so far suggests a link between GRKs and preeclampsia-related hypertension. Here, we demonstrate GRK2 expression is significantly downregulated (P < 0.0001) in preeclamptic placentae compared to normotensive controls. Knockdown or inhibition of GRK2 in placentae caused insufficient arterial remodeling and elevated trophoblast necroptosis in vivo. These further induced preeclampsia-like phenotype in mice: hypertension, proteinuria, and elevated pro-angiogenic cytokines. By human extra-villous invasive trophoblast cell line (HTR8/SVneo cells), we revealed the knockdown or inhibition of GRK2 triggered excessive death with typical necroptotic characteristics: nuclear envelope rupture and the activation of RIPK1, RIPK3, and MLKL. Necrostatin-1, an inhibitor of RIPK1, is able to restore the survival of trophoblasts. Together, our findings demonstrated that insufficient GRK2 activity compromises spiral artery remodeling and initiates necrotic events in placentae, thereby leading to preeclampsia. These findings advance our understanding of GRK2 in the pathogenesis of preeclampsia and could shed light on a potential treatment for preeclampsia.
| Item Type: | Article |
|---|---|
| Additional Information: | Data Availability Statement: The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s. |
| Uncontrolled Keywords: | cell death,grk2,necroptosis,preeclampsia,trophoblast,developmental biology,cell biology ,/dk/atira/pure/subjectarea/asjc/1300/1309 |
| Faculty \ School: | Faculty of Medicine and Health Sciences > Norwich Medical School |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 07 May 2025 15:30 |
| Last Modified: | 08 May 2025 07:30 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/99202 |
| DOI: | 10.3389/fcell.2021.694261 |
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