Role of GRK2 in Trophoblast Necroptosis and Spiral Artery Remodeling: Implications for Preeclampsia Pathogenesis
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 ini...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:0b3eaa4c576049f486867c818eab15352021-12-01T20:07:45ZRole of GRK2 in Trophoblast Necroptosis and Spiral Artery Remodeling: Implications for Preeclampsia Pathogenesis2296-634X10.3389/fcell.2021.694261https://doaj.org/article/0b3eaa4c576049f486867c818eab15352021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcell.2021.694261/fullhttps://doaj.org/toc/2296-634XImpaired 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.Zi LvZi LvZi LvLi-ling XiongLi-ling XiongLi-ling XiongXian QinHua ZhangHua ZhangHua ZhangXin LuoXin LuoXin LuoWei PengWei PengWei PengMark D. KilbyRichard SafferyPhilip N. BakerHong-bo QiHong-bo QiHong-bo QiFrontiers Media S.A.articleGRK2necroptosispreeclampsiatrophoblastcell deathBiology (General)QH301-705.5ENFrontiers in Cell and Developmental Biology, Vol 9 (2021) |
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GRK2 necroptosis preeclampsia trophoblast cell death Biology (General) QH301-705.5 |
| spellingShingle |
GRK2 necroptosis preeclampsia trophoblast cell death Biology (General) QH301-705.5 Zi Lv Zi Lv Zi Lv Li-ling Xiong Li-ling Xiong Li-ling Xiong Xian Qin Hua Zhang Hua Zhang Hua Zhang Xin Luo Xin Luo Xin Luo Wei Peng Wei Peng Wei Peng Mark D. Kilby Richard Saffery Philip N. Baker Hong-bo Qi Hong-bo Qi Hong-bo Qi Role of GRK2 in Trophoblast Necroptosis and Spiral Artery Remodeling: Implications for Preeclampsia Pathogenesis |
| description |
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. |
| format |
article |
| author |
Zi Lv Zi Lv Zi Lv Li-ling Xiong Li-ling Xiong Li-ling Xiong Xian Qin Hua Zhang Hua Zhang Hua Zhang Xin Luo Xin Luo Xin Luo Wei Peng Wei Peng Wei Peng Mark D. Kilby Richard Saffery Philip N. Baker Hong-bo Qi Hong-bo Qi Hong-bo Qi |
| author_facet |
Zi Lv Zi Lv Zi Lv Li-ling Xiong Li-ling Xiong Li-ling Xiong Xian Qin Hua Zhang Hua Zhang Hua Zhang Xin Luo Xin Luo Xin Luo Wei Peng Wei Peng Wei Peng Mark D. Kilby Richard Saffery Philip N. Baker Hong-bo Qi Hong-bo Qi Hong-bo Qi |
| author_sort |
Zi Lv |
| title |
Role of GRK2 in Trophoblast Necroptosis and Spiral Artery Remodeling: Implications for Preeclampsia Pathogenesis |
| title_short |
Role of GRK2 in Trophoblast Necroptosis and Spiral Artery Remodeling: Implications for Preeclampsia Pathogenesis |
| title_full |
Role of GRK2 in Trophoblast Necroptosis and Spiral Artery Remodeling: Implications for Preeclampsia Pathogenesis |
| title_fullStr |
Role of GRK2 in Trophoblast Necroptosis and Spiral Artery Remodeling: Implications for Preeclampsia Pathogenesis |
| title_full_unstemmed |
Role of GRK2 in Trophoblast Necroptosis and Spiral Artery Remodeling: Implications for Preeclampsia Pathogenesis |
| title_sort |
role of grk2 in trophoblast necroptosis and spiral artery remodeling: implications for preeclampsia pathogenesis |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/0b3eaa4c576049f486867c818eab1535 |
| work_keys_str_mv |
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