Review: Luteal prostaglandins: mechanisms regulating luteal survival and demise in ruminants.

The corpus luteum (CL) is critical for establishment and maintenance of pregnancy in all mammals. However, the fate of the CL in ruminants is dependent on the presence of a functional uterus or signals from a developing embryo to modify uterine function to ensure its own survival. The key molecule secreted by the uterus that must be modified is prostaglandin F2alpha (PGF2A). At the same time, there is evidence that mechanisms within the CL may influence the ability of PGF2A to cause luteolysis. This review focuses on prostaglandins and steroidogenic capacity as endogenous modulators of the sensitivity of the CL to exogenous PGF2A. Early luteal development and early pregnancy are two different luteal stages in which sensitivity of the CL to PGF2A renders it incapable, or less capable, respectively, of undergoing luteolysis in response to PGF2A compared to a midcycle CL. An analysis of molecular changes that occur during these two stages provides some novel insight into molecules and pathways worth exploring to explain the regulation of luteolytic capacity in corpora lutea of ruminants.

NR5A2 and potential regulatory miRNAs in the bovine CL during early pregnancy.

Progesterone, which is secreted from the corpus luteum, is indispensable for the establishment and maintenance of pregnancy. The orphan nuclear receptor subfamily 5 group A member 2 (NR5A2) is a regulator of murine luteinization, but neither its regulation nor its role in the fully differentiated, mature corpus luteum (CL) have been described. Therefore, the goal of this study was to profile abundance and investigate the regulation and functions of NR5A2 in the bovine CL. Treatment of cultured luteal steroidogenic cells with a pharmacological inhibitor of NR5A2 decreased progesterone production and tended to decrease abundance of HSD3B1 mRNA. Luteal NR5A2 mRNA increased and NR5A2 protein tended to increase between days 4 and 6 of the estrous cycle, coincident with increased steroidogenic capacity of the CL. Luteal NR5A2 mRNA decreased by 8 h after prostaglandin (PG) F2A injection. During early pregnancy, luteal NR5A2 mRNA was less on days 20 and 23 compared to day 14, but protein abundance did not change. Neither 1 nor 10 ng/mL interferon tau (IFNT) altered NR5A2 abundance in cultured luteal steroidogenic cells, but 10 ng/mL PGF2A decreased NR5A2. Because of discrepancies between mRNA and protein abundance of NR5A2, regulation by miRNA that changed during early pregnancy was investigated. miR-27b-3p, miR-432-5p, and miR-369-3p mimics decreased NR5A2 protein abundance and miR-369-3p also inhibited progesterone production. Overall, the results of this study show that NR5A2 may be maintained by miRNA during early pregnancy and may be an important regulator of luteal progesterone production.

Temporal changes in the corpus luteum during early pregnancy reveal regulation of pathways that enhance steroidogenesis and suppress luteolytic mechanisms†.

Although rescue of the corpus luteum (CL) is required for pregnancy, luteal function during maternal recognition of pregnancy remains largely unexplored. CL were collected from pregnant cattle on days 14, 17, 20, and 23, to encompass the maternal recognition of pregnancy period. Next-generation sequencing was used to profile mRNA abundance during this time, while tandem mass spectrometry and nanostring technology were used to profile proteins and miRNA, respectively. A total of 1157 mRNA were differentially abundant, while 27 miRNA changed, and 29 proteins tended to change. mRNA that increased were regulators of interferon signaling and DNA repair, while those that decreased were associated with luteolytic processes, such as calcium signaling and matrix metallopeptidase (MMP) signaling, indicating inhibition of these processes. One of these, MMP12, was regulated by prostaglandin F2A in vitro. mRNA that were maximally abundant on day 20 were primarily associated with immune processes. Two of these, C-C motif chemokine ligand 1 and NFKB inhibitor alpha, were regulated by interferon tau in vitro. MiRNA that increased were predicted to inhibit phosphatidylinositol signaling, while those that decreased may be negative regulators of steroidogenesis. One protein that was greater on day 20 than on day 14 was aldehyde dehydrogenase 1 family member A1 (ALDH1A1), which synthesizes retinoic acid. Pharmacological inhibition of this enzyme, or of retinoic acid receptor signaling, led to suppression of progesterone production in vitro. Overall, these data indicate that there are changes in the CL of pregnancy that are important for continued luteal function.