Intrauterine Inflammation Damages Placental Angiogenesis via Wnt5a-Flt1 Activation

Abstract

Intrauterine inflammation is the main reason for neonatal adverse outcomes and normal placenta perfusion plays an important role in fetal development. However, whether inflammation will affect placental angiogenesis and the underlying mechanism are still poorly understood. To investigate lipopolysaccharide (LPS)-induced intrauterine inflammation on placenta angiogenesis and Wnt5a-Flt1 expression. LPS-induced intrauterine inflammation rat model was established. Preterm rat outcomes were analyzed and angiogenesis of placenta villi was calculated by immunohistochemistry (IHC) of CD34 staining, and placenta Wnt5a-Flt1 expression was detected by western blot and IHC. Compared to control group, neonatal rats in LPS group showed higher death rate (1.4% vs 10.1%, p < 0.05) and lower birth weight (6.36 ± 0.48 vs 5.70 ± 0.67, p < 0.01); the villi vessel area and mean diameter in the placenta were significantly reduced in the LPS group (total area %, 16.7% ± 0.6% vs 8.7% ± 0.4%, p < 0.01, n = 9; mean diameter (pixel), 15.6 ± 0.5 vs 12.9 ± 0.3, p < 0.01, n = 9). Placenta Wnt5a-Flt1 expression was upregulated significantly (integrated optical density (IOD) in IHC: Wnt5a, 1667 ± 1204 vs 11,076 ± 4046, p < 0.05; Flt1, 2554 ± 466.2 vs 7998 ± 1613, p < 0.05; western blot: Wnt5a, 0.33 ± 0.05 vs 0.96 ± 0.06, p < 0.05; Flt1, 0.36 ± 0.15 vs 1.08 ± 0.08, p < 0.05). Intrauterine inflammation gave rise to offspring death rate and low birth weight; the mechanism might be disordered placental angiogenesis via Wnt5a-Flt1 activation triggered by inflammation.

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Availability of Data and Material

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Funding

This study received financial support from the National Natural Science Foundation of China (81873847) and Guangzhou Technology Program (201707010398, 201804010380).

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Contributions

Xu F, Zhong XM, and Zhang JY performed the experiments; Zhang Q analyzed data and collected the references; and Ren ZX was a major contributor in writing the manuscript. Yang J designed this study and edited the manuscript. All authors read and approved the final manuscript.

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Correspondence to J. Yang.

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Guangdong Women and Children Hospital Ethics committee

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201701079

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F. Xu and Z. X. Ren contributed equally to this work.

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Figure S1
figure6

Correlations between Wnt5a-Flt1 protein level (by IHC) and placenta vessel area in control group. N=9. A. No correlation was showed between Wnt5a and Flt1 expression. r=0.065, p=0.86; B. No correlation was showed between Wnt5a expression and placental vessel area. r=0.24, p=0.51. C. No correlation was showed between Flt1 expression and placental vessel area. r=0.35, p=0.36 (PNG 387 kb)

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Xu, F., Ren, Z.X., Zhong, X.M. et al. Intrauterine Inflammation Damages Placental Angiogenesis via Wnt5a-Flt1 Activation. Inflammation 42, 818–825 (2019). https://doi.org/10.1007/s10753-018-0936-y

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KEY WORDS

  • intrauterine inflammation
  • angiogenesis
  • placenta
  • preterm
  • Wnt5a
  • Flt1