Endometrial receptivity in cattle: the mutual reprogramming paradigm

Abstract

Prior to implantation in cattle, the mucous medium contained in the uterine lumen serves as a working interface for molecular exchange and signaling between the lining endometrium and the embryo. The composition of this luminal fluid changes temporally according to the secretory and reabsorptive activities of the uterus and the embryo, which are under complex regulation. Via this interface, both the embryo and the endometrium reprogram each other's functions to support pregnancy continuation beyond the pre-implantation period. More specifically, the embryo receives elongation signals and the uterus receives anti-luteolytic stimuli. Here, characteristics of the luminal compartment as well as the regulation of its composition to determine the pregnancy outcome will be discussed.

Keywords: cattle; embryo; endometrium; sex-steroids.

Figure 1. The mutual reprogramming paradigm for pre-implantation gestational success in cattle. Initial endometrial and the embryonic function are in response to both intrinsic (e.g., genetics) and extrinsic (e.g., sex-steroids [P4; progesterone, E2; estradiol], environment) stimuli. Default endometrial programming will lead to the production of luteolytic pulses of prostaglandin F2α (PGF) and the consequent regression of the corpus luteum. Embryo development outside of the reproductive tract (i.e., in vitro) stops prior to elongation. In vivo, mutual reprogramming stimuli between the embryo and the uterus are required for pre-implantation pregnancy to succeed. Molecular exchange needed for reprogramming takes place in the luminal fluid. LPS: Lipopolysaccharide, IFN-t : Interferon-tau, ISGs: Interferon stimulated genes.

Figure 2. Pregnancy losses between the day of embryo transfer and 30 days after estrus in recipients submitted to uterine luminal flushings (ULF) 1, 4 or 7 days after estrus. Mortality increased sharply when washings were conducted at the later moments [Adapted from Martins et al. (2018)]. *Means significantly different (P<0.05) comparing days 4 and 7 vs. control and day 1.

Figure 3. Temporal dynamics of uterine variables at proestrus, estrus, and metestrus. Sonograms used for scoring the uterine luminal fluid (ULF) accumulation on the entire organ (A) and for measuring the area of uterine luminal fluid accumulation on segment 4 of the uterine horn (B). Notice that patterns of fluid accumulation differ regionally in the uterus especially at metestrus when accumulation is minimum in the uterus as a whole but remains present at segment 4. Average temporal changes in the uterine luminal fluid score of the entire organ (C) and on segment 4 of the uterine horn [D; N=14, Adapted from Silva et al. (2021)].

Figure 4. Abundance of primary metabolite (A) and lipids (B) in luminal flushings collected post-mortem, at day four of the estrous cycle, from cows treated to ovulate a larger follicle (“receptive” luminal environment; R) or a smaller follicle (“low-receptivity” luminal environment; LR). For both A and B: Panel A. Total number of primary metabolites/lipids that displayed receptivity-related abundance (P<0.1) in the D4 uterine flushing. Panel B, C, D & E. Assignment of receptivity-associated compounds (P<0.1) to main biochemical metabolite and lipid classes. For pie-charts: (grey; ■) % for compounds with no receptivity-linked differences in concentrations; (blue; ■) % of compounds with greater abundance in R uterine flushing vs. LR uterine flushing; (red; ■) % of compounds with greater abundance in LR uterine flushing vs. R uterine flushing. For bar-charts: (R; □) receptive cows and (LR; ■) low receptive cows; bar represents mean ± standard error of the mean; Metabolite and lipid data were log10 transformed before plotting. Group means of compounds with * superscript are significantly different (P<0.05); Group means of compounds with $ superscript approached significance (P<0.1).