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. 2018 Sep;298(3):537-543.
doi: 10.1007/s00404-018-4802-9. Epub 2018 Jun 27.

Early missed abortion is associated with villous angiogenesis via the HIF-1α/VEGF signaling pathway

Zhifu Zhi  1 , Wenmei Yang  1 , Liling Liu  1 , XiaoLi Jiang  1 , Lihong Pang  2
Affiliations

Early missed abortion is associated with villous angiogenesis via the HIF-1α/VEGF signaling pathway

Zhifu Zhi et al. Arch Gynecol Obstet. 2018 Sep.

Abstract

Purpose: To analyze the effects of the hypoxia-inducible factor 1-alpha (HIF-1α)/vascular endothelial growth factor (VEGF) signaling pathway on villous angiogenesis in early missed abortion.

Methods: Immunohistochemical assays were performed to detect the expression of micro-vessel density (MVD), HIF-1α, and VEGF in villous tissue samples from 30 missed abortions and 30 elective abortions in early pregnancy. We further analyzed the correlation between HIF-1α/VEGF and MVD. HTR8/SVneo cells were cultured under hypoxic (1%) or normoxic (20%) conditions, tube formation was investigated, and protein and mRNA level of HIF-1α/VEGF were determined using western blot and qRT-PCR. Finally, HIF-1α was knocked down with siRNA introduced into HTR8/SVneo cell line under hypoxia, and HIF-1α/VEGF expression and HTR8/SVneo tube formation were investigated.

Results: The expression of HIF-1α, VEGF, and MVD was lower in the missed abortion than in the elective abortion group. Correlational analysis showed that the expression of HIF-1α and VEGF was positively correlated with MVD in both groups. The levels of HIF-1α/VEGF mRNA and protein in HTR8/SVneo cells were significantly enhanced under hypoxia. HIF-1α knockdown with siRNA inhibited HIF-1α/VEGF mRNA and protein levels of HTR8/SVneo cells induced by hypoxia. Tube formation of HTR8/SVneo cells was significantly enhanced in hypoxic culture and was inhibited by HIF-1α knockdown with siRNA.

Conclusions: Our results reveal a novel role for HIF-1α/VEGF in regulating villous angiogenesis in early pregnancy and suggest that it may be a novel biomarker for missed abortion.

Keywords: Angiogenesis; HIF-1α; Missed abortion; VEGF.

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Conflict of interest statement

Conflict of interest

We declare that we have no conflict of interest.

Ethical approval

The study was approved by ethics committee of hospital.

Figures

Fig. 1
Fig. 1
Immunohistochemical staining for MVD, HIF-1α, and VEGF observed in the cytoplasm of syncytiotrophoblast cells and cytotrophoblast cells (a). (×400) Tissues from missed abortions showed lower MVD than with normal pregnancy (b). Normal pregnancy showed a high expression of HIF-1α and VEGF (c). *P < 0.05 vs. control group
Fig. 2
Fig. 2
MVD was correlated positively with HIF-1α and VEGF in the normal pregnancy group (a, b). MVD was also correlated positively with HIF-1α and VEGF in the missed abortion group (c, d)
Fig. 3
Fig. 3
Changes in HIF-1α and VEGF mRNA levels in each group as measured by quantitative PCR (a, b). Protein expression of HIF-1α and VEGF in differentially treated HTR8/SVneo cells as measured by western blot analyst (c). Protein expression relative to GAPDH of HIF-1α ratio (d), and VEGF ratio (e); Values are means mean ± standard deviation (n = 3 for each group). Negative control siRNA as NC control. *P < 0.05 vs. normoxic group; #P < 0.05 vs hypoxic group
Fig. 4
Fig. 4
Tube formation in HTR-8/SVneo cells. Representative photomicrographs after cultured for 12 h were shown, ×100. (a Normoxia, b hypoxia, c negative control siRNA as NC control, d siRNA). The columns indicate the number of branching points
See this image and copyright information in PMC

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