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A microenvironment of high lactate and low pH created by the blastocyst promotes endometrial receptivity and implantation

Published:September 20, 2021DOI:https://doi.org/10.1016/j.rbmo.2021.09.012

      Abstract

      Research question

      Is the blastocyst's idiosyncratic metabolic production of lactate, and creation of a specialized microenvironment at the implatation site, an important mediator of maternal–fetal signalling to promote endometrial receptivity and implantation?

      Design

      Hormonally primed ECC-1 and Ishikawa cells were used to assess functional changes to the endometrial epithelium after exposure to lactic acid (LA), LA with neutralized pH (nLA) or acidic pH (pHL). Tight junction integrity (transepithelial resistance [TER]), cellular proliferation or changes to gene expression by RT-PCR were analysed. The effect of LA on Endometrial stromal cells decidualization and migratory capacity, and HUVEC endothelial tube formation and angiogenesis, were also assessed.

      Results

      Treatment of ECC-1 cells with 2.5 mM (P = 0.0037), 5 mM (P = 0.0044), 7.5 mM and 10 mM (P = 0.003) (P = 0.0021) LA significantly decreased the rate of cellular proliferation while TER was decreased with exposure to 2.5 mM LA (P = 0.024), 5 mM LA (P = 0.021) and 7.5 mM LA (P = 0.033). Exposure to nLA or pHL had no effect on proliferation or TER. Upregulation of GLUT4 (P = 0.002), GPR81 (P = 0.048), VEGF, SNAI1 (both P < 0.001) and RELA (P = 0.023) mRNA expression was observed after exposure of Ishikawa cells to combined LA plus pHL. Lactic acid increased the migratory capacity of decidualized stromal cells (P = 0.047) without changing the extent of decidualization. HUVEC tube formation was significantly increased by 5 mM LA exposure (P = 0.009).

      Conclusions

      The identification of LA as an important mediator in the maternal–fetal dialogue underpinning implantation is supported. Further examination of the role of LA within the infertile or compromised endometrium could improve natural and assisted pregnancy success and needs further investigation.

      KEYWORDS

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      Biography

      Kathryn Gurner completed her PhD under the supervision of Professor David Gardner and Dr Alexandra Harvey at the University of Melbourne. Her research focuses on understanding both sides of the maternal–fetal dialogue underpinning embryonic development and implantation. She now works as a clinical research embryologist at Melbourne IVF.
      Key message
      The specialized microenvironment created by the blastocyst, characterized by high lactate and low pH, enhances endometrial remodelling for receptivity and implantation through functional changes to endometrial epithelial, stromal and endothelial cells. Therefore, lactic acid is to be an important signalling molecule underpinning the maternal–fetal dialogue at implantation.