2. Academic Validation
  3. GDF15 promotes trophoblast invasion and pregnancy success via the BMPR1A/BMPR2/p-SMAD1 pathway: Implications for recurrent miscarriage

GDF15 promotes trophoblast invasion and pregnancy success via the BMPR1A/BMPR2/p-SMAD1 pathway: Implications for recurrent miscarriage

  • Life Sci. 2025 Jun 15:371:123586. doi: 10.1016/j.lfs.2025.123586.
Shu-Han Yang 1,  Long Yang 1,  Yan Shi 1,  Hao-Ran Xu 1,  Jie Gan 1,  Jia-Xin Shi 2,  Yu Zhang 1,  Shi-Long Shen 1,  Jian Wang 3,  Xuan Zhang 4
Affiliations

Affiliations

  • 1 Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Medical School, Fudan University, Shanghai 200237, China.
  • 2 Institute of Pathology, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany.
  • 3 Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Medical School, Fudan University, Shanghai 200237, China. Electronic address: wangjian@sibpt.com.
  • 4 Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Medical School, Fudan University, Shanghai 200237, China. Electronic address: xuanzhang@sibpt.com.
PMID: 40157640 DOI: 10.1016/j.lfs.2025.123586
Abstract

Insufficient invasion of extravillous trophoblasts (EVTs) is associated with adverse pregnancy outcomes, including recurrent miscarriage (RM). Dysregulated expression of Growth Differentiation Factor 15 (GDF15) has been implicated in RM, but the underlying mechanism remains unclear. This study investigated the role of GDF15 in EVTs function and pregnancy outcomes. Spearman correlation analysis revealed a positive correlation between GDF15 and both BMPR1A and BMPR2 in EVTs. Furthermore, GDF15, BMPR1A, BMPR2, and phosphorylated SMAD1 (p-SMAD1) expression were significantly reduced in placental tissue from RM patients compared to Normal controls. Mechanistically, GDF15 activated the p-SMAD1 signaling pathway, inducing expression of its downstream targets, ID1 and Snail, and enhancing migratory and invasive activity in HTR-8/SVneo cells through interaction with the BMPR1A-BMPR2 receptor complex. Eriodictyol, a small molecule activator of BMPR2, was identified and shown to improve pregnancy outcomes in a mouse model of lipopolysaccharide (LPS)-induced early pregnancy loss (EPL). Eriodictyol can also enhance EVTs migration and invasion as well as activated the p-SMAD1 pathway by activating BMPR2. In conclusion, this study identifies BMPR1A as a receptor for GDF15 in EVTs and demonstrates that GDF15 promotes EVTs invasion and improves pregnancy outcomes via the BMPR1A/BMPR2/p-SMAD1 signaling axis. Eriodictyol, acting as a BMPR2 agonist, may offer a novel therapeutic strategy for preventing early pregnancy loss.

Keywords

Eriodictyol; Extravillous trophoblasts; GDF15; Recurrent miscarriage.

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