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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 1

Increased VEGF expression in decidual cells and sFLT1 expression in adjacent EVTs in preeclamptic women.

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Increased VEGF expression in decidual cells and sFLT1 expression in adja...
(A–H) VEGF and sFLT1 mRNA expression by ISH (basal plate). Dashed lines demarcate the border between decidua (De) and placenta. Vi, villi. In specimens from both control and preeclamptic (PE) women, VEGF was expressed specifically in maternal decidual cells (A, E, C, and G), and sFLT1 in adjacent EVTs (arrowheads; B, F, D, and H), but levels of both were dramatically elevated in preeclamptic specimens. (I–L) VEGF (I) and sFLT1 (K) ISH and CK7 IHC (J and L; sections adjacent to I and K). (M–P) VEGF (M), sFLT1 (N), PLGF (O), and VEGFB (P) total mRNA levels in placental basal plate samples from control and preeclamptic women, determined by qPCR. In preeclampsia, while levels of both VEGF and sFLT1 significantly increased, PLGF significantly decreased, and VEGFB remained unchanged. Results are mean ± SD. *P < 0.05 (n = 15). Scale bars: 100 μm.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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