Effects of prostaglandin F 2α  (PGF 2α ) on cell-death pathways in the bovine corpus luteum (CL)

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Abstract

Background

Prostaglandin F _2α (PGF _2α) may differentially affect viability of luteal cells by inducing either proliferation or cell death (via apoptosis or necroptosis). The diverse effects of PGF _2α may depend on its local vs. systemic actions. In our study, we determined changes in expression of genes related to: (i) apoptosis: caspase (CASP) 3, CASP8, BCL2 associated X (BAX), B-cell lymphoma 2 (BCL2) and (ii) necroptosis: receptor-interacting protein kinase (RIPK) 1, RIPK3, cylindromatosis (CYLD), and mixed lineage kinase domain-like (MLKL) in the early and mid-stage corpus luteum (CL) that accompany local (intra-CL) vs. systemic (i.m.) analogue of PGF _2α (aPGF _2α) actions. Cows at day 4 (n = 24) or day 10 (n = 24) of the estrous cycle were treated by injections as follows: (1) systemic saline, (2) systemic aPGF _2α (25 mg; Dinoprost), (3) local saline, (4) local aPGF _2α (2.5 mg; Dinoprost). After 4 h, CLs were collected by ovariectomy. Expression levels of mRNA and protein were investigated by RT-q PCR, Western blotting and immunohistochemistry, respectively.

Results

We found that local and systemic administration of aPGF _2α in the early-stage CL resulted in decreased expression of CASP3 ( P < 0.01), but CASP8 mRNA expression was up-regulated ( P < 0.05). However, the expression of CASP3 was up-regulated after local aPGF _2α treatment in the middle-stage CL, whereas systemic aPGF _2α administration increased both CASP3 and CASP8 expression ( P < 0.01). Moreover, we observed that both local and systemic aPGF _2α injections increased RIPK1, RIPK3 and MLKL expression in the middle-stage CL ( P < 0.05) while CYLD expression was markedly higher after i.m. aPGF _2α injections ( P < 0.001). Moreover, we investigated the localization of necroptotic factors (RIPK1, RIPK3, CYLD and MLKL) in bovine CL tissue after local and systemic aPGF _2α injections in the bovine CL.

Conclusion

Our results demonstrated for the first time that genes related to cell death pathways exhibit stage-specific responses to PGF _2α administration depending on its local or systemic actions. Locally-acting PGF _2α plays a luteoprotective role by inhibiting apoptosis and necroptosis in the early CL. Necroptosis is a potent mechanism responsible for structural CL regression during PGF _2α-induced luteolysis in cattle.

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Most cited references 9

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The corpus luteum: an ovarian structure with maternal instincts and suicidal tendencies.

S. Davis, Bo R Rueda (2002)

The corpus luteum is a unique hormone-regulated, transient reproductive gland that produces progesterone, a required product for the establishment and maintenance of early pregnancy. In the absence of pregnancy the corpus luteum will cease to produce progesterone and the structure itself will regress in size over time. Although the process of luteal regression has been studied for several decades, many of the regulatory mechanisms involved in loss of function and involution of the structure are incompletely understood. More importantly, we are far from understanding how these complex mechanisms function in unison. The factor or factors responsible for initiating and mediating luteolysis are no doubt more complex than originally envisioned. Further, efforts to elucidate the mechanisms responsible for luteolysis have been complicated by different interpretations of what is 'luteolysis', discrepancies between in vitro and in vivo studies, and subsequent biases which are associated with the different methods of analyses. Moreover, the complexity of the mechanisms which regulate the life span of the corpus luteum are compounded by the presence of a heterogeneous population of cells which often respond differentially to the same ligand or stimuli. Attempts to isolate specific luteal cell types for the intention of defining intracellular signaling mechanisms have yielded valuable information. However, studies of a specific cell type taken out of context are often subject to criticism. The most obvious being that the cells are no longer maintained within their three dimensional environment. Evaluation of the corpus luteum in vivo, is not without its criticisms either. A subtle change evoked within a subpopulation of cells can be overlooked if measured in whole tissue or in mixed cell preparations. Furthermore, treatment in vivo with a single agent/ligand (i.e., prostaglandin F2 alpha) may induce a secondary ligand that is ultimately responsible for the biological response. All arguments are valid and cannot be ignored. There are secondary levels of complexity in the corpus luteum brought about by the pleiotropic actions of specific ligands. For example, one ligand can be luteotropic to a steroid producing cell and cytotoxic to a luteal endothelial cell. Furthermore, a specific cell type within the corpus luteum may respond differentially depending on the developmental stage of the luteal phase (i.e., early, mid, or late luteal phase) suggesting that the intracellular signaling pathways are key to defining ligand-induced biological responses. The purpose of this review is to culminate what is known regarding signal transduction pathways activated by initiator(s) and/or mediators of luteolysis. We recognize that an all-inclusive review describing the molecular mechanisms involved in the development, maintenance and regression of the corpus luteum would be impossible within the context of this review. There are a number of recent reviews that discuss luteal development, luteal maintenance and luteolysis with emphasis on neuroendocrine events (1-3). Consequently, we have focused our review primarily on potential intracellular signaling events of proposed regulators and mediators of luteal regression. Where possible we have attempted to incorporate references that represent rodents, domestic farm animals and primates.

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Local changes in blood flow within the preovulatory follicle wall and early corpus luteum in cows.

Alicia T. R. Acosta, M Ohtani, A Miyamoto … (2003)

Haemodynamic changes are involved in the cyclic remodelling of ovarian tissue that occurs during final follicular growth, ovulation and new corpus luteum development. The aim of this study was to characterize the real-time changes in the blood flow within the follicle wall associated with the LH surge, ovulation and corpus luteum development in cows. Normally cyclic cows with a spontaneous ovulation (n = 5) or a GnRH-induced ovulation (n = 5) were examined by transrectal colour and pulsed Doppler ultrasonography to determine the area and the time-averaged maximum velocity (TAMXV) of the blood flow within the preovulatory follicle wall and the early corpus luteum. Ultrasonographic examinations began 48 h after a luteolytic injection of PGF(2alpha) analogue was given at the mid-luteal phase of the oestrous cycle. Cows with spontaneous ovulation were scanned at 6 h intervals until ovulation occurred. Cows with GnRH-induced ovulation were scanned just before GnRH injection (0 h), thereafter at 0.5, 1, 2, 6, 12, 24 h and at 24 h intervals up to day 5. Blood samples were collected at the same time points for oestradiol, LH and progesterone determinations. Cows with both spontaneous and GnRH-induced ovulation showed a clear increase in the plasma concentration of LH (LH surge) followed by ovulation 26-34 h later. In the colour Doppler image of the preovulatory follicle, the blood flow before the LH surge was detectable only in a small area in the base of the follicle. An acute increase in the blood flow velocity (TAMXV) was detected at 0.5 h after GnRH injection, synchronously with the initiation of the LH surge. At 12 h after the LH surge, the plasma concentrations of oestradiol decreased to basal concentrations. The TAMXV remained unchanged after the initial increase until ovulation, but decreased on day 2 (12-24 h after ovulation). In the early corpus luteum, the blood flow (area and TAMXV) gradually increased in parallel with the increase in corpus luteum volume and plasma progesterone concentration from day 2 to day 5, indicating active angiogenesis and normal luteal development. Collectively, the complex structural, secretory and functional changes that take place in the ovary before ovulation are closely associated with a local increase in the blood flow within the preovulatory follicle wall. The result of the present study provides the first visual information on vascular and blood flow changes associated with ovulation and early corpus luteum development in cows. This information may be essential for future studies involving pharmacological control of blood flow and alteration of ovarian function.

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Local changes in blood flow within the early and midcycle corpus luteum after prostaglandin F(2 alpha) injection in the cow.

M Ohtani, Akio Miyamoto, Nobuyuki Yoshizawa … (2002)

One of the postulated main luteolytic actions of prostaglandin (PG) F(2 alpha) is to decrease ovarian blood flow. However, before Day 5 of the normal cycle, the corpus luteum (CL) is refractory to the luteolytic action of PGF(2 alpha). Therefore, we aimed to determine in detail the real-time changes in intraluteal blood flow after PGF(2 alpha) injection at the early and middle stages of the estrous cycle in the cow. Normally cycling cows at Day 4 (early CL, n = 5) or Days 10--12 (mid CL, n = 5) of the estrous cycle (estrus = Day 0) were examined by transrectal color and pulsed Doppler ultrasonography to determine the blood flow area, the time-averaged maximum velocity (TAMXV), and the volume of the CL after an i.m. injection of a PGF(2 alpha) analogue. Ultrasonographic examinations were carried out just before PG injection (0 h) and then at 0.5, 1, 2, 4, 8, 12, 24, and 48 h after the injection. Blood samples were collected at each of these times for progesterone (P) determination. The ratio of the colored area to a sectional plane at the maximum diameter of the CL was used as a quantitative index of the changes in blood flow within the luteal tissue. Blood flow within the midcycle CL initially increased (P < 0.05) at 0.5-2 h, decreased at 4 h to the same levels observed at 0 h, and then further decreased to a lower level from 8 h (P < 0.05) to 48 h (P < 0.001). Plasma P concentrations decreased (P < 0.05) from 4.7 +/- 0.5 ng/ml (0 h) to 0.6 +/- 0.2 ng/ml (24 h). The TAMXV and CL volume decreased at 8 h (P < 0.05) and further decreased (P < 0.001) from 12 to 24 h after PG injection, indicating structural luteolysis. These changes were not detected in the early CL, in which luteolysis did not occur. In the early CL, the blood flow gradually increased in parallel with the CL volume, plasma P concentration, and TAMXV from Day 4 to Day 6. The present results indicate that PGF(2 alpha) induces an acute blood flow increase followed by a decrease in the midcycle CL but not in the early CL. This transitory increase may trigger the luteolytic cascade. The lack of intraluteal vascular response to PG injection in the early CL appears to be directly correlated with the ability to be resistant to PG.

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Author and article information

Contributors

Katarzyna Karolina Piotrowska-Tomala: +48-89-539-31-30 , k.piotrowska-tomala@pan.olsztyn.pl

Journal

Journal ID (nlm-ta): BMC Vet Res

Journal ID (iso-abbrev): BMC Vet. Res

Title: BMC Veterinary Research

Publisher: BioMed Central (London )

ISSN (Electronic): 1746-6148

Publication date (Electronic): 21 November 2019

Publication date PMC-release: 21 November 2019

Publication date Collection: 2019

Volume: 15

Electronic Location Identifier: 416

Affiliations

Department of Reproductive Immunology and Pathology, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, 10-747 Tuwima 10 St ., 10 -, 748 Olsztyn, Poland

Article

Publisher ID: 2167

DOI: 10.1186/s12917-019-2167-3

PMC ID: 6873574

PubMed ID: 31752870

SO-VID: da8bd3a4-cf72-46c8-b380-0ee77a1d6531

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 15 July 2019

Date accepted : 6 November 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100004281, Narodowe Centrum Nauki;

Award ID: 2017/X/NZ9/00363

Award ID: 2018/29/B/NZ9/00391

Award Recipient : Katarzyna Karolina Piotrowska-Tomala Dariusz Jan Skarzynski

Funded by: FundRef http://dx.doi.org/10.13039/501100008648, Krajowy Naukowy Osrodek Wiodacy;

Award ID: Dec: 05-1/KNOW2/2015

Custom metadata

ScienceOpen disciplines: Veterinary medicine

Keywords: necroptosis,ripks,apoptosis,prostaglandin f2α,bovine cl

Data availability:

ScienceOpen disciplines: Veterinary medicine

Keywords: necroptosis, ripks, apoptosis, prostaglandin f2α, bovine cl

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