E-Poster Presentation ESA-SRB-ANZBMS 2021

A high lactate low pH microenvironment created by the blastocyst promotes endometrial receptivity and implantation. (#593)

Kathryn H Gurner 1 , Jemma Evans 2 3 , Jennifer Hutchison 2 3 , Alexandra J Harvey 1 , David K Gardner 1 4
  1. School of Biosciences, University of Melbourne, Parkville, VIC, Australia
  2. Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, VIC, Australia
  3. Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia
  4. Melbourne IVF, East Melbourne, VIC, Australia

Successful embryo implantation requires a synchronized dialogue between the receptive endometrium and blastocyst via locally produced soluble mediators. At the time of implantation, the blastocyst produces significant amounts of lactate, creating a microenvironment around the embryo characterized by high lactate (LA) and low pH. Whilst historically considered a ‘byproduct’ of metabolism, identification of a lactate specific receptor, GPR81, and recent work in cancer cells has established LA as an important signalling molecule, with roles in angiogenesis, ECM breakdown and immunosuppression, processes that are vital for successful implantation. Hence, this study investigated the role of LA as an early embryonic signal to facilitate endometrial remodelling for receptivity and implantation.

 

Functional changes to the endometrium were assessed by exposure of hormonally primed ECC-1 and Ishikawa cells to LA, LA + neutralized pH (nLA) or acidic pH (pHL), before analysis of tight junction integrity (TER), proliferation and gene expression changes. LA’s effects on endometrial stromal cell decidualization, migration, as well as HUVEC endothelial tube formation/angiogenesis, were also determined.

 

TER and proliferation were downregulated in ECC-1 cells exposed to 2.5, 5 and 7.5mM LA (P<0.01), while exposure to nLA or pHL alone had no significant effect. Upregulation of GLUT4, GPR81, VEGF, SNAI1, and RELA mRNA expression was observed following exposure of Ishikawa cells to combined LA + pHL (P<0.05), while MCT-1 expression decreased. Additionally, LA increased the migration of decidualized stromal cells (P<0.05) without changing the extent of decidualization. HUVEC tube formation was significantly increased by 5mM LA exposure (P<0.01).

 

Together, these results suggest that the specialized microenvironment created by the blastocyst, of both high lactate and low pH, enhances endometrial remodelling for receptivity and implantation through functional changes to epithelial, stromal and endothelial cells in the endometrium. Therefore, LA appears to be an important signalling molecule in the maternal-fetal dialogue underpinning implantation.