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Loss of placental growth factor ameliorates maternal hypertension and preeclampsia in mice
Jacqueline G. Parchem, … , Peter Carmeliet, Raghu Kalluri
Jacqueline G. Parchem, … , Peter Carmeliet, Raghu Kalluri
Published September 4, 2018
Citation Information: J Clin Invest. 2018;128(11):5008-5017. https://doi.org/10.1172/JCI99026.
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Research Article Reproductive biology Article has an altmetric score of 6

Loss of placental growth factor ameliorates maternal hypertension and preeclampsia in mice

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Abstract

Preeclampsia 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.

Authors

Jacqueline G. Parchem, Keizo Kanasaki, Megumi Kanasaki, Hikaru Sugimoto, Liang Xie, Yuki Hamano, Soo Bong Lee, Vincent H. Gattone, Samuel Parry, Jerome F. Strauss, Vesna D. Garovic, Thomas F. McElrath, Karen H. Lu, Baha M. Sibai, Valerie S. LeBleu, Peter Carmeliet, Raghu Kalluri

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Figure 1

Elevation of serum sFlt-1 and placental Flt-1 levels in pregnant PlGF KO mice.

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Elevation of serum sFlt-1 and placental Flt-1 levels in pregnant PlGF KO...
(A) Serum VEGF levels measured by ELISA in nonpregnant WT (n = 6) and PlGF KO (n = 9) and pregnant WT (n = 10) and PlGF KO (n = 10) mice. (B) Serum sFlt-1 levels (ELISA) in nonpregnant and pregnant WT (n = 4) and PlGF KO (n = 5) mice. (C) Immunohistochemistry for Flt-1 shows increased Flt-1 protein expression in PlGF KO placentas and decidua compared with WT. Spongiotrophoblast cells marked by yellow asterisks, parietal trophoblast giant cells by yellow arrowheads. Solid lines mark the border between the junctional zone and the decidua. D, decidua; JZ, junctional zone. Scale bars: 100 μm (top row); 25 μm (bottom row). (D) Immunohistochemistry for Flt-1 in the kidney glomerulus showing similar expression in PlGF KO and WT (upper panels). Secondary antibody–only control shown in lower panels. Scale bars: 25 μm. Results are shown as mean ± SD. One-way ANOVA. **P < 0.01, ***P < 0.001, ****P < 0.0001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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