Role of GRK2 in Trophoblast Necroptosis and Spiral Artery Remodeling: Implications for Preeclampsia Pathogenesis

Zi Lv; Li-Ling Xiong; Xian Qin; Hua Zhang; Xin Luo; Wei Peng; Mark D Kilby; Richard Saffery; Philip N Baker; Hong-Bo Qi

doi:10.3389/fcell.2021.694261

Role of GRK2 in Trophoblast Necroptosis and Spiral Artery Remodeling: Implications for Preeclampsia Pathogenesis

Front Cell Dev Biol. 2021 Nov 30:9:694261. doi: 10.3389/fcell.2021.694261. eCollection 2021.

Authors

Zi Lv^{1

2

3}, Li-Ling Xiong^{1

2

3}, Xian Qin⁴, Hua Zhang^{1

2

3}, Xin Luo^{1

2

3}, Wei Peng^{1

2

3}, Mark D Kilby⁵, Richard Saffery⁶, Philip N Baker⁷, Hong-Bo Qi^{1

2

3}

Affiliations

¹ Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
² State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing Medical University, Chongqing, China.
³ Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.
⁴ Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
⁵ Centre for Women's and New Born Health, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom.
⁶ Cancer, Disease and Developmental Epigenetics, Murdoch Children's Research Institute, Parkville, VIC, Australia.
⁷ College of Medicine, Biological Sciences and Psychology, University of Leicester, Leicester, United Kingdom.

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.

Keywords: GRK2; cell death; necroptosis; preeclampsia; trophoblast.