Endometrial receptivity in cattle: the mutual reprogramming paradigm

Thematic Section: IX International Symposium on Animal Biology of Reproduction (ISABR 2022) • Anim. Reprod. 19 (4) • 2022 • https://doi.org/10.1590/1984-3143-AR2022-0097 copy

Endometrial receptivity in cattle: the mutual reprogramming paradigm

Authorship SCIMAGO INSTITUTIONS RANKINGS

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; endometrium; sex-steroids; embryo

Authorship

Mario Binelli ^**Corresponding author: mario.binelli@ufl.edu

Department of Animal Sciences, University of Florida, Gainesville, Florida, USAUniversity of FloridaUSAGainesville, Florida, USADepartment of Animal Sciences, University of Florida, Gainesville, Florida, USA

https://orcid.org/0000-0002-5995-3944

Felipe Alves Correa Carvalho Silva

https://orcid.org/0000-0002-9189-0912

Cecilia Constantino Rocha

https://orcid.org/0000-0001-7244-1137

Thiago Martins

Department of Animal and Dairy Sciences and Brown Loam Experiment Station, Mississippi State University, Raymond, Mississippi, USAMississippi State UniversityUSARaymond, Mississippi, USADepartment of Animal and Dairy Sciences and Brown Loam Experiment Station, Mississippi State University, Raymond, Mississippi, USA

https://orcid.org/0000-0001-7580-1871

Mariana Sponchiado

Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida, USAUniversity of Florida, GainesvilleUSAFlorida, USADepartment of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida, USA

https://orcid.org/0000-0002-1293-9010

Veerle Van Hoeck

Kemin Europa, Animal Nutrition and Health EMENA, Toekomstlaan, Herentals, BelgiumAnimal Nutrition and Health EMENABelgiumToekomstlaan, Herentals, BelgiumKemin Europa, Animal Nutrition and Health EMENA, Toekomstlaan, Herentals, Belgium

https://orcid.org/0000-0003-1931-5136

Andrey Cordeiro

Centro de Ciências Biológicas e da Natureza, Universidade Federal do Acre, Rio Branco, AC, BrasilUniversidade Federal do AcreBrasilRio Branco, AC, BrasilCentro de Ciências Biológicas e da Natureza, Universidade Federal do Acre, Rio Branco, AC, Brasil

https://orcid.org/0000-0003-0667-1086

Meghan Campbell

https://orcid.org/0000-0002-6704-1427

Jo L. M. R. Leroy

Department of Veterinary Sciences, Gamete Research Centre, University of Antwerp, Wilrijk, BelgiumUniversity of AntwerpBelgiumWilrijk, BelgiumDepartment of Veterinary Sciences, Gamete Research Centre, University of Antwerp, Wilrijk, Belgium

https://orcid.org/0000-0002-2262-9403

Francisco Peñagaricano

Department of Animal and Dairy Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USAUniversity of Wisconsin-MadisonUSAMadison, Wisconsin, USADepartment of Animal and Dairy Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA

https://orcid.org/0000-0001-6661-3991

Guilherme Pugliesi

Departamento de Reprodução Animal, Faculdade de Medicina Veterinária e Zootecnia, Universidade de São Paulo, Pirassununga, SP, BrasilUniversidade de São PauloBrasilPirassununga, SP, BrasilDepartamento de Reprodução Animal, Faculdade de Medicina Veterinária e Zootecnia, Universidade de São Paulo, Pirassununga, SP, Brasil

https://orcid.org/0000-0001-5739-0677

*Corresponding author: mario.binelli@ufl.edu

Conflicts of interest: The authors have no conflict of interest to declare.

Author contributions

MB: Conceptualization, Funding acquisition, Supervision, Writing – original draft, Writing – review & editing; FACCS: Formal analysis, Methodology, Writing – review & editing; CCR: Formal analysis, Methodology, Writing – review & editing; TM: Formal analysis, Methodology, Writing – review & editing; MS: Formal analysis, Methodology, Writing – review & editing; VVH: Formal analysis, Methodology, Writing – review & editing; AC: Formal analysis, Methodology; MC: Formal analysis, Methodology; JLMRL: Formal analysis, Methodology, Writing – review & editing; FP: Formal analysis, Methodology, Writing – review & editing; GP: Formal analysis, Methodology, Writing – review & editing.

SCIMAGO INSTITUTIONS RANKINGS

Figures

Figures (4)

Thumbnail

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.

Thumbnail

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)Martins T, Pugliesi G, Sponchiado M, Gonella-Diaza AM, Ojeda-Rojas OA, Rodriguez FD, Ramos RS, Basso AC, Binelli M. Perturbations in the uterine luminal fluid composition are detrimental to pregnancy establishment in cattle. J Anim Sci Biotechnol. 2018;9(1):70. http://dx.doi.org/10.1186/s40104-018-0285-6. PMid:30356865.
http://dx.doi.org/10.1186/s40104-018-028... ]. *Means significantly different (P<0.05) comparing days 4 and 7 vs. control and day 1.

Thumbnail

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)Silva FACC, Silva GF, Vieira BS, Laurindo A No, Rocha CC, Turco EG, Nogueira GP, Pugliesi G, Binelli M. Peri-estrus ovarian, uterine, and hormonal variables determine the uterine luminal fluid metabolome in beef heifers. Biol Reprod. 2021;105(5):1140-53. http://dx.doi.org/10.1093/biolre/ioab149. PMid:34350935.
http://dx.doi.org/10.1093/biolre/ioab149... ].

Thumbnail

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).

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)Martins T, Pugliesi G, Sponchiado M, Gonella-Diaza AM, Ojeda-Rojas OA, Rodriguez FD, Ramos RS, Basso AC, Binelli M. Perturbations in the uterine luminal fluid composition are detrimental to pregnancy establishment in cattle. J Anim Sci Biotechnol. 2018;9(1):70. http://dx.doi.org/10.1186/s40104-018-0285-6. PMid:30356865.
http://dx.doi.org/10.1186/s40104-018-028... ]. *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)Silva FACC, Silva GF, Vieira BS, Laurindo A No, Rocha CC, Turco EG, Nogueira GP, Pugliesi G, Binelli M. Peri-estrus ovarian, uterine, and hormonal variables determine the uterine luminal fluid metabolome in beef heifers. Biol Reprod. 2021;105(5):1140-53. http://dx.doi.org/10.1093/biolre/ioab149. PMid:34350935.
http://dx.doi.org/10.1093/biolre/ioab149... ].

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).

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[1] *Corresponding author: mario.binelli@ufl.edu