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Endometrial VEGF induces placental sFLT1 and leads to pregnancy complications
Xiujun Fan, … , James C. Cross, Nihar R. Nayak
Xiujun Fan, … , James C. Cross, Nihar R. Nayak
Published October 20, 2014
Citation Information: J Clin Invest. 2014;124(11):4941-4952. https://doi.org/10.1172/JCI76864.
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Research Article

Endometrial VEGF induces placental sFLT1 and leads to pregnancy complications

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Abstract

There is strong evidence that overproduction of soluble fms-like tyrosine kinase-1 (sFLT1) in the placenta is a major cause of vascular dysfunction in preeclampsia through sFLT1-dependent antagonism of VEGF. However, the cause of placental sFLT1 upregulation is not known. Here we demonstrated that in women with preeclampsia, sFLT1 is upregulated in placental trophoblasts, while VEGF is upregulated in adjacent maternal decidual cells. In response to VEGF, expression of sFlt1 mRNA, but not full-length Flt1 mRNA, increased in cultured murine trophoblast stem cells. We developed a method for transgene expression specifically in mouse endometrium and found that endometrial-specific VEGF overexpression induced placental sFLT1 production and elevated sFLT1 levels in maternal serum. This led to pregnancy losses, placental vascular defects, and preeclampsia-like symptoms, including hypertension, proteinuria, and glomerular endotheliosis in the mother. Knockdown of placental sFlt1 with a trophoblast-specific transgene caused placental vascular changes that were consistent with excess VEGF activity. Moreover, sFlt1 knockdown in VEGF-overexpressing animals enhanced symptoms produced by VEGF overexpression alone. These findings indicate that sFLT1 plays an essential role in maintaining vascular integrity in the placenta by sequestering excess maternal VEGF and suggest that a local increase in VEGF can trigger placental overexpression of sFLT1, potentially contributing to the development of preeclampsia and other pregnancy complications.

Authors

Xiujun Fan, Anshita Rai, Neeraja Kambham, Joyce F. Sung, Nirbhai Singh, Matthew Petitt, Sabita Dhal, Rani Agrawal, Richard E. Sutton, Maurice L. Druzin, Sanjiv S. Gambhir, Balamurali K. Ambati, James C. Cross, Nihar R. Nayak

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Figure 8

Effects of placental sFlt1 knockdown with or without endometrial VEGF overexpression.

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Effects of placental sFlt1 knockdown with or without endometrial VEGF ov...
(A–L) Placental sFlt1 knockdown. Upon placenta-specific sFLT1 shRNA expression, widespread hemorrhaging in the fetus (B) and at the placental-decidual junction (D) was observed on GD18 compared with controls (A and C). Histological examination of sFLT1 shRNA–expressing placentas revealed extraordinary dilation of some maternal blood sinuses (arrowheads) in the labyrinth (E and F) and fibrin deposition (arrow) in these spaces (G and H). (I and J) MSB staining revealed extravasated fibrin (arrow) in adjacent areas. Placental sFlt1 knockdown did not affect implantation rate (K), whereas the fetal resorption rate significantly increased (L). (M–V) Placental sFlt1 knockdown enhanced the deleterious effects in Endo-VEGF animals. Pregnancies surviving to GD16 exhibited (M) excessive vaginal bleeding and (N–P) termination of pregnancy or resorption (arrows denote resorption sites) as well as (Q) widespread and extensive hemorrhaging in fetuses and placentas (arrowheads) and in deciduas at the maternal-fetal junction (asterisk). Histological examination (R–T) revealed widespread dilation and congestion of maternal blood sinuses (arrowheads) in the labyrinth, venous sinuses, and veins at maternal-fetal junctions, and MSB staining (U and V) demonstrated extensive fibrin extravasation (arrows) in the labyrinth and at the maternal-fetal junction. Results are mean ± SD. *P < 0.05 (n = 15). Scale bars: 2 mm (A–D); 500 μm (E, F, and R); 50 μm (G–J); 100 μm (S–V).

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

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