Lv Zi, Xiong Li-Ling, Qin Xian, Zhang Hua, Luo Xin, Peng Wei, Kilby Mark D, Saffery Richard, Baker Philip N, Qi Hong-Bo
Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing Medical University, Chongqing, China.
Front Cell Dev Biol. 2021 Nov 30;9:694261. doi: 10.3389/fcell.2021.694261. eCollection 2021.
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 ( < 0.0001) in preeclamptic placentae compared to normotensive controls. Knockdown or inhibition of GRK2 in placentae caused insufficient arterial remodeling and elevated trophoblast necroptosis . 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.
绒毛外滋养层细胞侵袭受损和严重氧化应激表明子痫前期胎盘形成不良，子痫前期不仅是一种危及生命的妊娠高血压疾病。以往研究报道，G蛋白偶联受体激酶（GRKs）在引发高血压和高血压性肾损伤中起关键作用，但目前几乎没有证据表明GRKs与子痫前期相关高血压之间存在联系。在此，我们证明与血压正常的对照组相比，子痫前期胎盘组织中GRK2表达显著下调（<0.0001）。胎盘组织中GRK2的敲低或抑制导致动脉重塑不足和滋养层细胞坏死性凋亡增加。这些进一步在小鼠中诱导出子痫前期样表型：高血压、蛋白尿和促血管生成细胞因子升高。通过人绒毛外侵袭性滋养层细胞系（HTR8/SVneo细胞），我们发现GRK2的敲低或抑制引发了具有典型坏死性凋亡特征的过度死亡：核膜破裂以及RIPK1、RIPK3和MLKL的激活。RIPK1抑制剂Necrostatin-1能够恢复滋养层细胞的存活。总之，我们的研究结果表明GRK2活性不足会损害螺旋动脉重塑并引发胎盘组织中的坏死事件，从而导致子痫前期。这些发现增进了我们对GRK2在子痫前期发病机制中的理解，并可能为子痫前期的潜在治疗提供线索。
