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Browsing by Author "Kanasaki, Keizo"
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Item Loss of placental growth factor ameliorates maternal hypertension and preeclampsia in mice(American Society for Clinical Investigation, 2018-11-01) Parchem, Jacqueline G.; Kanasaki, Keizo; Kanasaki, Megumi; Sugimoto, Hikaru; Xie, Liang; Hamano, Yuki; Lee, Soo Bong; Gattone, Vincent H.; Parry, Samuel; Strauss, Jerome F.; Garovic, Vesna D.; McElrath, Thomas F.; Lu, Karen H.; Sibai, Baha M.; LeBleu, Valerie S.; Carmeliet, Peter; Kalluri, Raghu; Anatomy and Cell Biology, IU School of MedicinePreeclampsia remains a clinical challenge due to its poorly understood pathogenesis. A prevailing notion is that increased placental production of soluble fms-like tyrosine kinase-1 (sFlt-1) causes the maternal syndrome by inhibiting proangiogenic placental growth factor (PlGF) and VEGF. However, the significance of PlGF suppression in preeclampsia is uncertain. To test whether preeclampsia results from the imbalance of angiogenic factors reflected by an abnormal sFlt-1/PlGF ratio, we studied PlGF KO (Pgf-/-) mice and noted that the mice did not develop signs or sequelae of preeclampsia despite a marked elevation in circulating sFLT-1. Notably, PlGF KO mice had morphologically distinct placentas, showing an accumulation of junctional zone glycogen. We next considered the role of placental PlGF in an established model of preeclampsia (pregnant catechol-O-methyltransferase-deficient [COMT-deficient] mice) by generating mice with deletions in both the Pgf and Comt genes. Deletion of placental PlGF in the context of COMT loss resulted in a reduction in maternal blood pressure and increased placental glycogen, indicating that loss of PlGF might be protective against the development of preeclampsia. These results identify a role for PlGF in placental development and support a complex model for the pathogenesis of preeclampsia beyond an angiogenic factor imbalance.Item STOX1 deficiency is associated with renin-mediated gestational hypertension and placental defects(American Society for Clinical Investigation, 2021-01-25) Parchem, Jacqueline G.; Kanasaki, Keizo; Lee, Soo Bong; Kanasaki, Megumi; Yang, Joyce L.; Xu, Yong; Earl, Kadeshia M.; Keuls, Rachel A.; Gattone, Vincent H., II.; Kalluri, Raghu; Anatomy and Cell Biology, School of MedicineThe pathogenesis of preeclampsia and other hypertensive disorders of pregnancy remains poorly defined despite the substantial burden of maternal and neonatal morbidity associated with these conditions. In particular, the role of genetic variants as determinants of disease susceptibility is understudied. Storkhead-box protein 1 (STOX1) was first identified as a preeclampsia risk gene through family-based genetic linkage studies in which loss-of-function variants were proposed to underlie increased preeclampsia susceptibility. We generated a genetic Stox1 loss-of-function mouse model (Stox1 KO) to evaluate whether STOX1 regulates blood pressure in pregnancy. Pregnant Stox1-KO mice developed gestational hypertension evidenced by a significant increase in blood pressure compared with WT by E17.5. While severe renal, placental, or fetal growth abnormalities were not observed, the Stox1-KO phenotype was associated with placental vascular and extracellular matrix abnormalities. Mechanistically, we found that gestational hypertension in Stox1-KO mice resulted from activation of the uteroplacental renin-angiotensin system. This mechanism was supported by showing that treatment of pregnant Stox1-KO mice with an angiotensin II receptor blocker rescued the phenotype. Our study demonstrates the utility of genetic mouse models for uncovering links between genetic variants and effector pathways implicated in the pathogenesis of hypertensive disorders of pregnancy.