1. Top of page
  2. Contents
  3. Introduction
  4. Regulation of Luteal Formation and Angiogenesis by Local Factors
  5. Conclusions and Practical Implications
  6. Funding
  7. Conflicts of interest
  8. Author Contributions
  9. References

The bovine corpus luteum (CL) is a transient gland with a life span of only 18 days in the cyclic cow. Mechanisms controlling CL development and secretory function may involve factors produced both within and outside this gland. Although luteinizing hormone (LH) surge is the main trigger of ovulation and granulosa cells luteinization, many locally produced agents such as arachidonic acid (AA) metabolites, growth factors and cytokines were shown to complement gonadotropins action in the process of CL development. Bovine CL is a highly vascular gland, where the very rapid angiogenesis rate (until Day 5 of the cycle) results in the development of a capillary network, endowing this gland with one of the highest blood flow rate per unit mass in the body. Angiogenesis in the developing CL is later followed by either controlled regression of the microvascular tree in the non-fertile cycle or maintenance and stabilization of the blood vessels, as seen during pregnancy. Different luteal cell types (both steroidogenic and accessory luteal cells: immune cells, endothelial cells, pericytes and fibroblasts) are involved in the pro- and/or anti-angiogenic responses. The balance between pro- and anti-angiogenic responses to the main luteolysin – prostaglandin F2α (PGF2α) could be decisive in whether or not PGF2α induces CL regression. Fibroblast growth factor-2 (FGF2) may be one of the factors that modulate the angiogenic response to PGF2α. Manipulation of local production and action of FGF2 will provide new tools for reproductive management of dairy cattle. Luteolysis is characterized by a rapid decrease in progesterone production, followed by structural regression. Factors like endothelin-1, cytokines (tumour necrosis factorα, interferons) and nitric oxide were all shown to play critical roles in functional and structural regression of the CL by inhibiting steroidogenesis and inducting apoptosis.


  1. Top of page
  2. Contents
  3. Introduction
  4. Regulation of Luteal Formation and Angiogenesis by Local Factors
  5. Conclusions and Practical Implications
  6. Funding
  7. Conflicts of interest
  8. Author Contributions
  9. References

The corpus luteum (CL) is a transient endocrine gland not only responsible for progesterone synthesis (P4), which is indispensible for pregnancy establishment and maintenance, but also presents additional roles regulating the ovarian cycle and fertility in general. The CL formation, triggered by the luteinizing hormone (LH) surge, is a complex process involving mechanisms similar to wound healing and tumour formation with robust angiogenesis. The new CL develops from cells that remain in the follicle following oocyte extrusion during ovulation, but is eventually composed of multiple, distinctive cell types including steroidogenic cells (small and large luteal cells) and non-steroidogenic cells (endothelial cells, pericytes, fibrocytes and immune cells; Meidan et al. 1999, 2005; Bauer et al. 2001; Townson et al. 2002; Skarzynski and Okuda 2010). In the cow, P4 concentrations continuously increase until Day 14 of the oestrous cycle, even though the CL volume does not significantly increases after Day 7 (Sangsritavong et al. 2002). The increase in volume and circulating P4 during the first 7 days is likely due to a dramatic enhance in P4 production and hypertrophy in the large luteal cells. The circulating P4 profile is now recognized to have a central role in reproductive efficiency of lactating dairy cows, with particular importance for the interactions between reproduction and nutrition, health and management (Thatcher et al. 2006). During its lifespan, the CL undergoes a period of extremely rapid growth that involves hypertrophy, proliferation and differentiation of the steroidogenic cells, as well as extensive angiogenesis (Shirasuna et al. 2012a).

The CL is a highly vascular gland and a site of intense angiogenesis. It is the development of an elaborate network of blood vessels that endows the CL with one of the highest blood flow rates per unit mass in the body (Wiltbank et al. 1988). The newly formed vessels are essential to guarantee the necessary supply of nutrients and hormones that allow its proper function. The short period of angiogenesis (until Day 5 of the cycle in the cow) is later followed either by maintenance and stabilization of the vasculature, as seen in case of pregnancy, or by a controlled regression of the microvascular tree in the non-fertile cycle, which occurs during luteolysis.

Because of its unique importance for successful pregnancy, the formation and maintenance of the CL are among the most significant and closely regulated events in mammalian reproduction. Inadequate CL function was found to be a major constraint to productivity in various animal species (Spencer et al. 2007).

Although it is generally accepted that the LH surge is the main trigger of ovulation and the resulting process of luteinization, many locally produced agents such as growth factors and cytokines were shown to complement gonadotropins' action in the process of CL development (Korzekwa et al. 2004; Schams and Berisha 2004). Indeed, in various animals, insufficient CL was documented despite what appeared to be a normal LH surge.

Regulation of Luteal Formation and Angiogenesis by Local Factors

  1. Top of page
  2. Contents
  3. Introduction
  4. Regulation of Luteal Formation and Angiogenesis by Local Factors
  5. Conclusions and Practical Implications
  6. Funding
  7. Conflicts of interest
  8. Author Contributions
  9. References

Growth factors

Vascular endothelial growth factor A (VEGFA), a member of the VEGF family, occupies a central place among the regulators of angiogenesis in the ovary. Also known as vascular permeability factor (VPF), VEGFA is the major specific stimulator of endothelial cell proliferation and migration, acting through two tyrosine kinase receptors, VEGFR-1 (flt-1) and VEGFR-2 (KDR; Ferrara and Davis-Smyth 1997).

In the CL, VEGFA expression (mRNA and protein) is upregulated soon after the LH surge and remains elevated at least until the mid-late luteal phase (Berisha et al. 2000; Jiang et al. 2011; Tesone et al. 2005). In most species, VEGFA mRNA is detected in the new CL, in granulosa-derived lutein cells (Wulff et al. 2001; Berisha et al. 2000). Additionally, several studies had verified that VEGFA is essential for optimal CL function (Fraser et al. 2010; Yamashita et al. 2008). Daily intraluteal injections with VEGFA antibody (from Day 1 to Day 8) markedly decreased the bovine CL volume, plasma P4 concentration and steroidogenesis (Yamashita et al. 2008). The in vivo observations on the VEGF inhibitory effect on plasma P4 are most probably due to the disruption of luteal blood vessels. However, in the mare, VEGFA could directly stimulate P4 and prostaglandin E2 (PGE2) production by in vitro cultured luteal cells (Galvão et al. 2012a). Also, critical is the up-regulation of VEGFA transcription by hypoxia-inducible factor (HIF)-1α protein (Hewitson et al. 2007). The hypoxia-induced up-regulation of VEGFA occurs at the transcriptional level by HIF1 proteins, which bind to the hypoxia response element region in the VEGF promoter (Hewitson et al. 2007; Kim et al. 2008). The biological activity of secreted VEGFA is further influenced by hypoxia-inducible expression of the Flt-1 and KDR receptors (Kim et al. 2008). At the early stage of luteal development, due to insufficient blood supply, hypoxic conditions exist in the CL (Tesone et al. 2005) and act as a potent stimulus for VEGF expression by granulosa/luteal cells (Kim et al. 2009; Klipper et al. 2010). Remarkably, in the ovary, unlike in other tissues, LH/hCG alongside with hypoxia can augment VEGF expression (Christenson and Stouffer 1997; Klipper et al. 2010). Indeed, chronic or acute exposure to hCG directly stimulates VEGF production and secretion by granulosa cells of several mammalian species, including farm animals (Christenson and Stouffer 1997; Klipper et al. 2010).

Fibroblast growth factor 2 (FGF2) is another potent luteal pro-angiogenic factor. It stimulates the proliferation of endothelial cells derived from bovine corpora lutea (Woad et al. 2012; Zalman et al. 2012) and is expressed at particularly high levels during the bovine follicular–luteal transition (Robinson et al. 2007). The FGF family encompasses 23 structurally related heparin-binding angiogenic peptides (Ornitz and Itoh 2001), which are pleiotropic factors that act on various cells, including endothelial cells. Intracellularly, FGFs interact with heparin sulphate proteoglycans (HSPGs) and FGF receptors with tyrosine kinase activity. The CL, especially at early stages of its development, is a rich source FGF2 (Robinson et al. 2007). In fact, FGF2 was first extracted and identified in the bovine CL (Gospodarowicz et al. 1985; ). In association with VEGF, FGF2 provides the essential pro-angiogenic support to the developing CL necessary to establish its complex vascular system (Schams and Berisha 2004; Robinson et al. 2007; Yamashita et al. 2008; Woad et al. 2009). As a matter of fact, it was also shown that FGF2 was a potent inducer of angiogenic characteristics in luteal derived endothelial cells, enhancing cell migration and proliferation (Zalman et al. 2012). However, FGF2 is known to be more potent at inducing endothelial cell proliferation than VEGF. Treatment with a FGF receptor signalling inhibitor almost completely blocked luteal endothelial network formation in vitro (Woad et al. 2009, 2012). This occurred even in the presence of exogenous angiogenic growth factor VEGFA, indicating that FGF2 is critical for the formation of luteal endothelial networks (Woad et al. 2009). Furthermore, mentioned findings also suggest that these factors could have complementary rather than redundant actions (Woad et al. 2009). The significance of FGF2 to luteal development was also demonstrated when neutralization of FGF2, achieved by injecting FGF2 antibody into the developing bovine CL, altered luteal growth and function, probably by inhibiting the establishment of a new vascular network (Yamashita et al. 2008).

Fibroblast growth factor 2 levels, like those of VEGFA, are elevated during luteinization. However, FGF2 peaks at a very early luteal phase (Robinson et al. 2007) strikingly overlapping the hypoxic conditions in the CL and the profile of HIF-1α. Nevertheless, the relationship between FGF2 and hypoxia in the CL has not been thoroughly studied yet. Also, the cellular distribution of these two pro-angiogenic factors is different. While VEGFA is more abundant in the steroidogenic luteal cells, FGF2 is highly expressed in both steroidogenic and endothelial cells types with a clear preference towards the endothelial cells. A limited number of studies have shown that FGF2 may also affect granulosa and luteal cell functions and illustrate pleiotropic nature of this growth factor.


Immune cells present in the CL throughout the oestrous cycle are considered to be determinant for ovarian function regulation (Penny et al. 1999; Townson and Liptak 2003). Generally, immune cells action in the CL is carried out through the production and secretion of cytokines tumour necrosis factor-α (TNF), interferon-γ (IFNγ) or interleukins (ILs), and other factors as: PGs, granulocyte–macrophage colony–stimulating factor (GM-CSF), macrophage colony–stimulating factor (M-CSF) and angiogenic factors (Pate and Keyes 2001; Skarzynski and Okuda 2010). Cytokines role on luteal function regulation in cattle has been thoroughly reviewed before (Pate and Keyes 2001; Okuda and Sakumoto 2003; Skarzynski and Okuda 2010). The mRNA of TNF, IFNγ and IL-1 is transcribed not only in immune cells but also in steroidogenic and endothelial cells (Sakumoto et al. 2000, 2011; Okuda and Sakumoto 2003; Nishimura et al. 2004). This finding suggests that, besides being determinant during luteal regression, these cytokines may also regulate luteal steroidogenesis as well as vascular function (Petroff et al. 1999; Skarzynski et al. 2003a, 2007; Korzekwa et al. 2008a). Tumour necrosis factor-α was shown to control several ovarian processes like follicular development, ovulation and luteal regression, by acting specifically on different receptors: the TNF-RI (death receptors), and the TNF-RII (survival receptors; Terranova 1997). Furthermore, numerous in vitro studies have evidenced that TNF induces luteal cell death exclusively in association with INFγ or other intraluteal factors, that is, endothelin (EDN)-1 (reviewed by Pate and Keyes 2001; Meidan et al. 2005; Skarzynski and Okuda 2010).

As a pleitropic factor, TNF can exert opposite biological functions. Previous in vivo studies confirmed TNF luteolytic action and its influence on bovine CL lifespan (Skarzynski et al. 2003a). In fact, lower doses of TNF increased prostaglandin F2α (PGF2α) and nitrite/nitrate (stable NO metabolites) levels, decreased P4 level and, consequently, shortened the oestrous cycle. Interestingly, TNF administration in high doses stimulated the synthesis of P4 and PGE2, prolonging the lifespan of bovine CL (Skarzynski et al. 2003a, 2007; Korzekwa et al. 2008a). These in vivo results were recently in vitro supported (Szostek et al. 2011). Still regarding TNF luteotropic action, the TNF at higher concentrations increased P4 output by microdialysed bovine CL (Fig. 1). Thus, TNF may act in the bovine CL in a dose-dependent manner, supporting steroidogenic luteal cells function including PGE2 and P4 stimulation during the luteal phase and early pregnancy (Sakumoto et al. 2000; Skarzynski et al. 2003a, 2007; Korzekwa et al. 2008a).


Figure 1. Effect of tumour necrosis factor (TNF) α on pulsatile progesterone (P4) output by bovine corpora lutea (CL) in vitro. The bovine CLs (Day 8–10 of the oestrous cycle) were cut vertically, through the face of the apex, in four pieces and perfuzed in a microdialysis system (MDS) with TNF at luteotropic dose 1 μg/ml for 4 h (b). Saline was run as a control (a). The pulses of P4 were determined when a minimum of two or more adjacent measurements presented a concentration value 25% higher than the mean of all the 12 measurements. The asterisks indicate the significant statistical differences in the pulses of P4 (p < 0.05). Adapted and modified from Szostek et al. (2011)

Download figure to PowerPoint

Not only steroidogenic cells can be a target of cytokine actions within the bovine CL. Specific binding sites for TNF are also present in luteal endothelial cells derived from bovine CL (Petroff et al. 1999; Okuda et al. 1999; Friedman et al. 2000; Korzekwa et al. 2011). Cytokines may stimulate cell proliferation or induce apoptosis of bovine luteal endothelial cells (Friedman et al. 2000; Davis et al. 2003; Pate and Keyes 2001). Also, TNF contributes to the production of PGE2, PGI2 and PGF2α in in vitro cultured bovine luteal endothelial cells (Okuda et al. 1999; Korzekwa et al. 2011). Therefore, several cytokines (including TNF) could also promote the formation of bovine CL, as it was recently reported for equine CL (Galvão et al. 2012a,b).


A peptide implicated in ovulation and luteal formation is the endothelin (EDN)-2. It represents a member of a 21-amino acid peptides family that includes also EDN1 and EDN3 (Inoue et al. 1989; Meidan and Levy 2007). Both EDN1 and EDN2 are the forms expressed in the ovary, presenting the closest amino acidic structure and differing only by two amino acids (aa). Considering EDN3, it differs from other EDNs by six aa (Inoue et al. 1989; Meidan and Levy 2007). Similarly to EDN1, EDN2 is known for its strong vasoconstricting activity. Nevertheless, it acts in a different physiological context and is produced not only by the epithelial cells but also in granulosa cells (Ko et al. 2006; Kim et al. 2009; Klipper et al. 2010).

The multiple effects of EDNs are mediated by G protein-coupled receptors, termed ETA and ETB. The coupling of activated EDN receptors to multiple G-proteins may explain the involvement of EDNs in diverse cellular processes (Inoue et al. 1989; Meidan and Levy 2002). Ko et al. (2006) firstly reported that EDN2, localized in the granulosa cells, abruptly increased after hCG injection into PMSG-primed rats. Treatment with mixed ETA/ETB EDN receptor antagonist before ovulation caused a substantial delay in ovulation and decreased the number of released oocytes in mice and rats (Ko et al. 2006; Palanisamy et al. 2006). Which receptor type mediates EDN2 action in bovine granulosa cells is still unclear and awaits further research. In cows, EDN2 mRNA displayed a transient pattern of expression during the luteal phase. The highest EDN2 mRNA levels were observed in the early CL, 60 h post-GnRH-induced ovulation and also in cyclic CL collected before the Day 5 of the cycle. The EDN2 mRNA then declined to basal levels in mid-luteal phase (Klipper et al. 2010). Notably, unlike EDN2, EDN1 mRNA was not elevated at any time point during GnRH-induced folliculo-luteal transition (Klipper et al. 2010). In the early CL, EDN2 mRNA was identified mainly in bovine luteal steroidogenic cells, but not in endothelial cells that expressed the EDN1 gene (Klipper et al. 2010). Similarly, in pre-ovulatory follicles, EDN2 was expressed in the granulosa cells (Klipper et al. 2010) and not in the vascular theca interna, similarly to what was observed in mice (Ko et al. 2006; Palanisamy et al. 2006). Besides LH, hypoxia was found to be a strong inducer of EDN2 transcription in all species examined thus far (Kim et al. 2009; Klipper et al. 2010). It is noteworthy that these same factors (LH and hypoxia) have been long known to induce VEGF in the CL (Christenson and Stouffer 1997). Interestingly, not only LH/hCG but also EDN2 itself could also directly induce VEGF in granulosa cells (Klipper et al. 2010). Like LH/hCG, EDN2 induced in these cells proliferation as well as up-regulation of VEGF and cyclooxygenase-2 (mRNA and protein levels). Together, these data suggest that elevated EDN2 in the early bovine CL, triggered by the LH surge and hypoxia, may facilitate CL formation by promoting angiogenesis, cell proliferation and differentiation.

Phospholipids metabolites: prostaglandins, leukotrienes and lisophosphatidic acid

Prostaglandins and leukotriens (LTs) are produced from AA, which is released from the phospholipid membrane (Hansel 1996). A rate-limiting enzyme of PG synthesis is the PG-endoperoxide synthase 2 (PTGS2), responsible for AA conversion into PGG2. During the oestrous cycle in the cow, mRNA expression of PTGS2 is higher in the early CL than in other phases (Tsai et al. 1996; Kobayashi et al. 2002). Cell-specific synthases and isomerases, such as PGES and PGFS, are responsible for PGE2 and PGF2α production, respectively. Both PGs are secreted in the bovine CL throughout the luteal phase. However, the highest PGs output level and expression of their synthetic enzymes were found in the early luteal phase (Milvae and Hansel 1983; Arosh et al. 2004).

Prostaglandin E2 is known as a luteotropic factor, as it stimulates the in vitro P4 production by bovine luteal steroidogenic cells (Alila et al. 1988; Kotwica et al. 2003; Bowolaksono et al. 2008). Moreover, PGE2 also promotes the secretion of luteotropic LTB4 from bovine steroidogenic and endothelial luetal cells, as well as inhibits cytokine-induced apoptosis in both early and mid-luteal stages (Korzekwa et al. 2010b; Bowolaksono et al. 2008).

The early bovine CL also produces the highest amount of PGF2α, comparing with other luteal phases (Milvae and Hansel 1983; Kobayashi et al. 2001). The PGF2α binds to the luteal cell through its specific plasma membrane receptor named PTGFR (Anderson et al. 2001). In vivo studies demonstrated that PGF2α acutely decreased P4 secretion by inhibiting 3βHSD and StAR mRNA expression and other rate-limiting steroidogenic enzymes (Tsai and Wiltbank 1998; Atli et al. 2012). Simultaneously, PGF2α was shown to promote the production of luteolytic mediators, like EDN1 (reviewed by Meidan et al. 1999; Meidan and Levy 2002, 2007), LTC4 (Korzekwa et al. 2010a,b) and nitric oxide (NO; Skarzynski et al. 2003b; Shirasuna et al. 2008; Lee et al. 2010). Other in vitro reports demonstrated that PGF2α stimulates P4 secretion by cultured bovine luteal cells (Miyamoto et al. 1993; Mamluk et al. 1999; Bah et al. 2006; Korzekwa et al. 2008b; Pate et al. 2012). Likewise, PGF2α and PGE2 can suppress apoptosis of bovine steroidogenic and endothelial cells (Bowolaksono et al. 2008). Both PGs at the concentration of 1 μm increased cell viability and suppressed cell death, decreased caspase (CASP) 3 and CASP8 mRNA expression, and inhibited TNF and IFNγ induced CASP3 activity (Bowolaksono et al. 2008). Nonetheless, Pate et al. (2012) have recently proposed that the observed PGF2α luteotropic effects are mainly related with its utilization at high concentrations, which may represent supraphysiologic doses considerably higher than those seen during spontaneous luteolysis in vivo. At such levels (1 μm), PGF2α could bind PGE2 receptor rather than PGF receptor (Rao 1974; Anderson et al. 1999) and, once activated, PGE2 receptor could stimulate P4 production. Still, it should be noticed that the referred PGF2α concentration decreased P4 secretion by CL slices (Girsh et al. 1995; Doerr et al. 2008). This emphasizes the importance of other cell types, besides steroidogenic cells (endothelial and immune cells), for the modulation of PGF2α actions in the bovine CL.

Leukotrienes are synthesized by 5-lipoxygenase (5-LO), which catalyses the conversion of AA into LTA4. The intermediary product LTA4 is further hydrolysed to LTB4 or conjugated with glutathione to form LTC4 and its metabolites: LTD4 and LTE4 (Zipser and Laffi 1985). Messenger RNA for LT receptors (both for LTB4 and C4) and 5-LO is expressed in the bovine steroidogenic and endothelial cells of the CL, throughout the luteal phase (Korzekwa et al. 2010a,b). Leukotriene B4 was shown to promote bovine CL growth by stimulating PGE2 secretion in different in vitro conditions, where just luteal endothelial cells from early and mid CL stages were cultured (Korzekwa et al. 2010b), or all luteal cell populations were used (Blair et al. 1997). In mid-luteal stage, LTB4 also presents a luteotropic action, stimulating P4 output from the bovine CL (Korzekwa et al. 2010b). Contrarily, LTC4 increases PGF2α production by bovine luteal endothelial cells (Korzekwa et al. 2010b) and by microdialysed CL (Blair et al. 1997), suggesting its putative luteolytic action. Regarding NOEDN-1 production, LTC4 was shown to stimulate its secretion by endothelial cells from Day 2–4 CL (Korzekwa et al. 2010b). In conclusion, on one hand, endogenous LTC4 inhibits P4 secretion in the oestrous cycle, as its antagonist – Azelastine elevated P4 output, and on the other hand, LTB4 action enhances P4 secretion, as its antagonist – Dapsone inhibited P4 output in the oestrous cycle in vivo (Korzekwa et al. 2010a). Further studies are needed to better understand LTs role in CL angiogenesis and/or angioregression.

Lysophosphatidic acid (LPA), the biologically active phospholipid, is critical for several physiological and pathological processes, including inflammation, cell proliferation and differentiation, cytoskeletal rearrangement, angiogenesis, wound healing and cancer invasion. The LPA has been shown to affect female reproductive functions in several mammalian species, including the cow (Woclawek-Potocka et al. 2009, 2010). In vivo, LPA administered into the abdominal aorta stimulated P4 and PGE2 secretion during the luteal phase and prolonged bovine CL lifespan (Woclawek-Potocka et al. 2009, 2010). Recently, it has been confirmed that bovine CL presents a dual function regarding LPA action, representing both the site of LPA synthesis and the target for LPA action (Kowalczyk-Zieba et al. 2012a). Lysophosphatidic acid concentrations in the CL tissue increased towards the end of the cycle and were stable during early pregnancy. No changes in the expression of LPA receptors (LPARs) occurred during the oestrous cycle. However, expressions of LPAR2 and LPAR4 on Days 17–19 of pregnancy were higher than those on the respective days of the oestrous cycle, and even higher than those on Days 8–10 of pregnancy. It was also shown that LPA stimulates P4 production and 3βHSD, at mRNA and protein levels, in the luteal cells from Days 8–10 of the oestrous cycle (Fig. 2; Kowalczyk-Zieba et al. 2012a).


Figure 2. Effect of lysophosphatic acid (LPA) on progesterone (P4) production by the cultured bovine luteal cells at mid-luteal phase. Lysophosphatic acid (10–6 m), interferone τ and both reagents together were added 12-h before the end of culture. (a) P4 concentrations in the culture medium; (b) mRNA expression of 3β-hydroxysteroid dehydrogenase (3β-HSD) in the cells (real-time PCR); (c) Densitometric quantification of 3β-HSD protein content in the luteal cells (Western blot). All values are expressed as means ± SEM. Different letters indicated significant differences (p < 0.05). Adapted and modified from Kowalczyk-Zieba et al. (2012a)

Download figure to PowerPoint

In humans, LPA in preovulatory follicles may be important for luteal angiogenesis via increasing IL-8 and IL-6 levels (Chen et al. 2008). Thus, LPA could be a potential modulator of endothelial cell growth and function. Panetti et al. (1997) demonstrated that LPA at the dose of 3 μm is a potent stimulator of bovine aortic endothelial cells (BAEC) growth. Also, endothelial NOS (eNOS) was forcefully activated by LPA, in BAEC (Kou et al. 2002). Conversely, thrombospondin-1 (TSP1), a known inhibitor of angiogenesis and endothelial cell proliferation, inhibited LPA-stimulated mitogenesis of BAEC (Panetti et al. 1997). Moreover, in vitro studies reported that LPA inhibited NO and TNF/IFNγ cytokine-induced apoptosis via abrogation of the stimulatory effect of these factors on mRNA and protein levels of BAX/Bcl2 ratio, Fas–FasL system and pro-inflammatory cytokine receptors (Kowalczyk-Zieba et al. 2012b). Evidently, LPA supported bovine luteal cells survival. Therefore, it could be suggested that LPA is an additional auxiliary luteosupportive factor in the bovine CL (Kowalczyk-Zieba 2012a,b).

Sex hormones

Rekawiecki and co-workers recently reviewed the regulation of P4 synthesis and its auto/paracine actions in the bovine CL (Rekawiecki et al. 2008). Progesterone receptor (PR) is expressed in both small and large luteal cells, and also in vascular endothelial cells (Sakumoto et al. 2010). Bovine CL exhibited specific nuclear staining for PR, which was more evident on Days 5–10 after ovulation in cycle animals, comparing with other stages of the oestrous cycle or pregnancy (Kotwica et al. 2004). Messenger RNA level of PR significantly changes during the oestrous cycle, presenting the highest transcription level in the early CL of the cow (Sakumoto et al. 2010). It is well known that P4 considerably influences the vascular function of the female reproductive system, throughout the oestrous cycle (Reynolds and Ford 1984). Progesterone has also been shown to regulate cell survival in the bovine CL (Friedman et al. 2000; Rueda et al. 2000; Okuda et al. 2004; Rueda et al. 2000). Use of P4 antagonists promoted DNA fragmentation (Rueda et al.2000) and P4 could abolish TNF-induced apoptosis of luteal endothelial cells (Friedman et al. 2000). Furthermore, P4 inhibited cytokine-induced apoptosis in bovine luteal cells through the inhibition of Fas and CASP3 mRNA expression (Okuda et al. 2004).

Considering P4 production, it has been shown that this steroid is able to regulate its own synthesis in the bovine CL (Kotwica et al. 2004). After 6 h of incubation with P4, its concentration in CL slices, as well as 3β-HSD activity, increased over 3-times when compared with the control. These effects were seen only in CL from Days 5–10 of the cycle. To avoid the putative influence of secreted P4 present in the culture medium after in vitro culture, cells were treated with a specific P4 antagonist (onapristone). As a consequence, in early luteal cells, secretion of P4, OT, PGF2α and PGE2 was reduced by onapristone (Skarzynski and Okuda 1999; Okuda et al. 2004). Undoubtedly, these data suggest that P4 promotes its own synthesis and secretion from bovine CL, with special significance during CL growth and development.

Another important finding related with P4 action in CL regards the NO generation system. The inducible NO synthase (iNOS) isoform was also inhibited by auto/paracrine P4 actions in bovine luteal endothelial cells (Yoshioka et al. 2012). Moreover, an antagonist of P4 blocked the suppressive effect of P4 on NO generation. Interestingly, eNOS expression and its activity were unaffected by P4, in the bovine CL (Yoshioka et al. 2012). One may conclude that P4 plays important roles in regulating CL function by controlling NO generation and action.

Prostaglandin F2α-induced corpus luteum regression

In the absence of an embryonic signal, the CL will regress. Luteal regression is necessary for the initiation of a new reproductive cycle. Nonetheless, extension of luteal life span and P4 secretion are absolutely required for pregnancy maintenance.

In a non-fertile cycle, PGF2α is secreted from the uterus and then initiates a series of events culminating in its demise (McCracken et al. 1999). Initially, luteal function is impaired and plasma P4 declines (Niswender et al. 2000). This is followed by apoptosis and structural elimination of the CL (Meidan et al. 1999; Yadav et al. 2002; Korzekwa et al. 2006). Exogenously administered PGF2α can initiate luteolysis only in the mature CL (McCracken et al. 1999). For instance, the bovine CL is resistant (or refractory) to the luteolytic actions of PGF2α before Day 5 of the oestrous cycle (Pursley et al. 1995; Tsai and Wiltbank 1998; Levy et al. 2006). The refractory period exists even though early bovine CL contains the receptors for PGF2α and can respond to its injection, by changing hormone secretion and gene expression patterns (Pursley et al. 1995; Levy et al. 2006). The reader is also referred to previous reviews on the luteolytic actions of PGF2α (McCracken et al. 1999; Niswender et al. 2000; Pate 2003; Schams and Berisha 2004; Meidan et al. 2005; Skarzynski and Okuda 2010; Shirasuna et al. 2012a, b; Pate et al. 2012).

Luteal stage-specific responses: Role of immune cells and angiogenic-related factors

Important novel findings regarding the luteolytic cascade and especially luteal stage-specific responses to PGF2α were recently made (Zalman et al. 2012; Atli et al. 2012). These studies attempted to identify PGF2α-induced changes in the transcriptome of bovine CL that are specific to mature CL (Mondal et al. 2011; Zalman et al. 2012). The microarray analysis was performed on PGF2α-responsive (Day 11) CL vs. refractory (Day 4) CL with GeneChip Bovine Genome Arrays. Accentuated gene expression response in Day 11 CL was accompanied by specific enrichment of PGF2α-regulated genes in distinctive gene ontology categories (Mondal et al. 2011). This study revealed that a considerable proportion of transcripts (25%) regulated at 4 h after PGF2α administration in Day 11 CL was similarly regulated in Day 4 CL that fails to regress (Mondal et al. 2011). The significant but transient gene expression response on day 4 suggested that, although initial response had occurred (at 4 h post-PGF2α administration), it was subsequently blocked or failed to amplify (at 24 h; Mondal et al. 2011). The mechanisms responsible for persistent enrichment of PGF2α-regulated genes in immune-related gene ontology categories in the Day 11 (PGF2α responsive) but not in the Day 4 (PGF2α refractory) CL may therefore be attributed to the enhanced crosstalk between immune cells and other luteal cell populations in the mature responsive CL. The induction of a battery of endothelial adhesion molecules such as chemokine (C-C motif) ligand 2 (CCL2), selectin (SEL) E and SELP would facilitate leucocyte recruitment and endothelial transmigration. Immune cells present in the mature CL (Townson et al. 2002; Bauer et al. 2001) may account for the more vigorous and persistent response to PG in the immune-related genes and the luteolytic cascade in Day 11 but not in Day 4 CL.

Interestingly, among the novel PGF2α-regulated genes recently described, quite few are involved in angiogenesis (being pro or anti-angiogenic; Fig. 3). Moreover, PG regulated the expression of angiogenesis-modulating factors in a luteal stage–dependent manner (Mondal et al. 2011; Zalman et al. 2012; Atli et al. 2012). A robust increase in FGF2 expression (mRNA and protein) occurred in the PGF2α-refractory Day 4 CL (Fig. 4). Elevation in FGF2 by PG at an early stage (particularly when no FGF2 inhibitors exist below) would act as a survival signal for both endothelial (Zalman et al. 2012; Woad et al. 2009) and steroidogenic cells of the CL (Grazul-Bilska et al. 1995). Support of blood vessel growth and its stabilization are expected to enhance the supply of nutrients and hormones to the gland, promoting its survival and contributing to its ability to become resistant to luteolysis. Activity of FGF2 in the extracellular milieu is controlled by its interaction with various extracellular matrix proteins and binding factors. Pentraxin-3 (PTX3) and TSP1 and TSP2 are prominent examples of such factors (Zalman et al. 2012; Fig. 3). It was found that inhibitors of FGF2 action, TSPs and their receptor (CD36), and (PTX3) were upregulated by PG specifically in Day 11 CL undergoing luteolysis (Zalman et al. 2012; Mondal et al. 2011), but not Day 4 CL. Furthermore, pronounced inhibition of FGF2-induced proliferation and/or migration of luteal endothelial cells was observed in vitro in response to TSP1 and PTX3 treatment. Dispersed luteal steroidogenic and endothelial cells alike expressed these genes, but TSP1 and FGF2 were more abundant in luteal endothelial cells. Reduced angiogenic support due to lower levels of FGF2 and VEGF, along with increased anti-angiogenic factors expression in Day11 PGF2α-responsive CL (Zalman et al. 2012; Atli et al. 2012), is expected to destabilize luteal vasculature and reduce its hormonal output characteristic of luteal regression. The increased angiopoietin-1 mRNA and protein, soon after PGF2α administration (Tanaka et al. 2004; Berisha et al. 2010), would also contribute to vessels destabilization. Only in mature gland these events along with increased blood vessel constriction by PGF2α-elevated EDN-1 would further reduce P4 secretion and promote regression of the CL (Meidan et al. 1999; Shirasuna et al. 2004; Doerr et al. 2008).


Figure 3. Anti-angiogenic genes expression in the bovine corpus luteum (CL) after prostaglandin (PG)F2α administration. Effects of i.m. administration of PGF2α on the abundance of mRNA for Pentraxin 3 (PTX3), thrombospondin (TSP)1 and TSP2, and their receptors (CD36) in PGF2α-refractory (Day 4) and PGF2α-responsive (Day 11) bovine CL collected before (0 h) and 4 h after PGF2α administration (n = 5 each). Data were normalized relative to the abundance of GPDH mRNA in the same samples. Letters denote significance for Day 4 (lowercase) and Day 11 (uppercase) CL (p < 0.05). Adapted and modified from Zalman et al. (2012)

Download figure to PowerPoint


Figure 4. Effects of prostaglandin (PG)F2α administration on fibroblastic growth factor (FGF)2 in PGF2α-refractory (Day 4) and PGF2α-responsive (Day 11) bovine corpus luteum (CL) collected before (0 h) and 4 h after PGF2α administration (n = 5 each). (a) The abundance of mRNA. Data were normalized relative to the abundance of GPDH mRNA in the same samples. Letters denote significance for Day 4 (lowercase) and Day 11 (uppercase) CL (p < 0.05). (b) Densitometric quantification of FGF2 protein content. Data were normalized relative to the abundance of β-Actin in the same samples. Significant (p < 0.05) difference from time 0. Inset: a representative Western blot for FGF2 with a major band at 18 kDa and actin (42 kDa) as the loading control is shown. Adapted and modified from Zalman et al. (2012)

Download figure to PowerPoint

These recent studies, based on transcriptome analyses, provide an insight into stage-specific responses to PGF2α and potential mediators of luteolysis (Zalman et al. 2012; Mondal et al. 2011). They reinforce the significant role of infiltration and activation of immune cell types suggested before (Shirasuna et al. 2012a; Pate 1995; Pate and Keyes 2001). Particularly, these reports introduce the concept that by tilting the balance between pro- and anti-angiogenic factors, PGF2α can potentially control the ability of the CL to resist or evolve towards luteolysis (Fig. 5).


Figure 5. Prostaglandin F2α (PGF2α) – induced luteolysis is related to its ability to promote or inhibit angiogenesis. A significant increase in pro-angiogenic fibroblast growth factor-2 (FGF2) occurred in the PG-refractory Day 4 corpus luteum (CL). Conversely, inhibitors of FGF2 action, thrombospondin (TSP)1 and 2, their receptor (CD36), and Pentraxin 3 (PTX3) were upregulated by PGF2α specifically in mature CL undergoing luteolysis. Vascular endothelial growth factor (VEGF) mRNA decreased 4 h post-PGF2α in both Day 4 and Day 11 CL. See text for detailed description

Download figure to PowerPoint

Death-ligands and their receptors in corpus luteum regression

Structural involution of the CL mainly involves apoptosis, or programmed cell death (Davis and Rueda 2002; Korzekwa et al. 2006). Apoptosis is defined as the fragmentation of DNA into oligonucleosomal units (Tilly 1996). During apoptosis, three major pathways have been identified: death receptor pathway, mitochondrial and nucleus pathways (Tilly 1996). Many cytokine receptors (Sakumoto et al. 2000; Petroff et al. 2001), second messengers including calcium ions [Ca2+] (Orrenius et al. 1992) and regulatory proteins (Antonsson 2001) are involved in apoptotic process. Fas ligand, a member of TNF super family, primarily engages its receptor (Fas) to induce apoptosis (Okuda and Sakumoto 2003). Members of the Bcl-2 protein family regulate the mitochondrial pathway of apoptosis (Antonsson 2001). Among other proteins, BAX – another member of Bcl-2 family – is also increased during CL regression (Sugino et al. 2005) and can ultimately lead to disruption of steroidogenesis and cell death (Davis and Rueda 2002). Ratio of pro-apoptotic BAX to anti-apoptotic Bcl-2 protein determines the induction of apoptosis (Anderson et al. 2001). Proteins of Bcl-2 family are caspase activators, resulting on the mitochondrial release of apoptogenic factors (Gross et al. 1999; Davis and Rueda 2002). The mechanism of apoptosis is known to occur as a cascade of sequential activation of initiator and effector caspases (Carambula et al. 2002). Caspases, a family of aspartic acid-specific cysteine proteases, are pivotal mediators of apoptosis during CL regression (Carambula et al. 2002). Of the 14 identified caspase family members, caspase-3 is the best-characterized enzyme, which participates in apoptotic signal transmission from the cytoplasm to the nucleus (Carambula et al. 2002; Davis and Rueda 2002). During luteal regression, besides apoptotic DNA degradation, cleavage of the putative caspase-3 substrate poly (ADP) ribose polymerase (PARP) also occurs (Davis and Rueda 2002).

Apoptosis of luteal cells and CL vascular regression are regulated by many different factors (see Fig. 6). A large number of factors have been implicated in PGF2α-induced structural luteolysis in cattle, such as pro-inflammatory cytokines (TNF, IFNγ), FasL (Davis and Rueda 2002; Okuda et al. 2002), EDN1 (Watanabe et al. 2006) and NO (Korzekwa et al. 2006). Messenger RNA for TNF, TNF death receptors (TNF-RI), Fas and IFNγ significantly increase during luteolysis in bovine CL (Sakumoto et al. 2000; Taniguchi et al. 2002; Neuvians et al. 2004; Korzekwa et al. 2008a). Contrary to the evidences that mRNA for TNF is present in the bovine CL throughout its lifespan (Petroff et al. 1999; Sakumoto et al. 2011), secreted TNF protein or its bioactivity could be detected only after the initial decrease in plasma P4 in bovine CL (Shaw and Britt 1995). This evidences the role of TNF on luteolysis promotion. As TNF and IFNγ receptors have been described in the microvasculature, their activated pathways can also modulate endothelial cell function (Okuda et al. 1999; Davis et al. 2003). Once endothelial cells are the first cellular content to undergo apoptosis in the regressing CL, these cytokines were considered to regulate bovine luteolysis, by inducing endothelial cells apoptosis (Sawyer et al. 1990; Okuda et al. 1999; Hojo et al. 2010). The above-mentioned cytokines,TNF and IFNγ), can also be integrated in the regulation of luteal endothelial cells (Korzekwa et al. 2006, 2011) and interact with EDN1 and PGF2α, inhibiting luteal steroidogenesis and stimulating luteal cells death (Ohtani et al. 2004; Okuda et al. 2002). In addition to TNFR, other cytokine receptors, second messengers including [Ca2+] and regulatory proteins are involved in apoptosis of steroidogenic and endothelial cells of the CL (Friedman et al. 2000; Petroff et al. 2001; Taniguchi et al. 2002). The FasL, a member of the TNF super family, primarily engages its receptor (Fas) to induce apoptosis (Taniguchi et al. 2002; Okuda et al. 2004). The expression of Fas mRNA was increased by IFNγ, and TNF augmented the stimulatory action of IFNγ on Fas expression (Taniguchi et al. 2002). Moreover, apoptotic bodies were observed in luteal cells treated with FasL, in the presence of IFNγ and/or TNF. Clearly, leucocyte-derived TNF and IFNγ play an important role on FasL-Fas-mediated luteal cell death in the bovine CL.


Figure 6. Possible luteolytic actions of pro-inflammatory cytokines (tumour necrosis factor α – TNFα, interferone γ – IFNγ), Fas Ligand (Fas-L) and nitric oxide in the bovine luteal cells. Pro-inflammatory cytokines, Fas-L and NO in concert, play a crucial role in both functional (inhibition of the basal and luteinizing hormone-stimulated P4 synthesis and regulation of corpus luteum blood flow) and structural luteolysis (induction of apoptosis of the luteal cells). They stimulate luteolytic arachidonic acid (AA) metabolites: prostaglandin (PG)F2α and leukotriene (LT)C4 and inhibit P4 secretion. Moreover, pro-inflammatory cytokines, Fas-L and NO are involved in induction of apoptosis stimulating caspase-3 expression and activity, stimulating BAX mRNA expression, and consequently, the ratio of pro-apoptotic BAX to anti-apoptotic BCL2 is increased. See text for detailed description. Modified and adapted from Sakumoto and Okuda (2003); Skarzynski et al. (2005), Skarzynski and Okuda (2010)

Download figure to PowerPoint

Another factor involved in apoptosis in the CL is the NO. Inhibition of NOS avoided the decrease in P4 and prolonged the luteal phase in cow (Jaroszewski and Hansel 2000). In fact, NO mediates PGF2α action during the first steps of the luteolytic cascade in cattle (Skarzynski et al. 2003a,b; Shirasuna et al. 2008; Acosta et al. 2009). Additionally, the molecular mechanisms of NO action during structural luteolysis were also demonstrated (Korzekwa et al. 2006). The NO strongly decreased luteal cell viability in vitro. Treatment of bovine luteal cells with NO donor more significantly increased DNA fragmentation than the one with PGF2α. Moreover, NO increased the mobilization of [Ca2+] in steroidogenic luteal cells. Although NO donor did not affect Fas-L and bcl-2 gene expression, it stimulated Fas and BAX mRNA and CASP3 expression. Also, the ratio of bcl-2 to BAX mRNA level decreased in cells treated with NO donor (Korzekwa et al. 2006). The overall results suggest that NO plays a crucial role for regulating the oestrous cycle, not only during the first steps of functional luteolysis (Skarzynski et al. 2003b; Shirasuna et al. 1998; Acosta et al. 2009), but also as a potent mediator of PGF2α in structural luteolysis by inducing apoptosis of steroidogenic CL cells in cattle (Korzekwa et al. 2006; Fig. 6). Similar effects of NO in steroidogenic luteal cells apoptosis induction have been reported in another species (Jee et al. 2003; Preutthipan et al. 2004; Al-Gubory et al. 2005).

Conclusions and Practical Implications

  1. Top of page
  2. Contents
  3. Introduction
  4. Regulation of Luteal Formation and Angiogenesis by Local Factors
  5. Conclusions and Practical Implications
  6. Funding
  7. Conflicts of interest
  8. Author Contributions
  9. References

Natural PGF2α as well as analogues of PGF2α (aPGF2α) are used for oestrous cycle synchronization in cattle (McCracken et al. 1999). Synchronization programmes have become standard approaches in the current breeding management of cows in dairy herds of most worldwide countries. Many are based on protocols that allow timed inseminations to circumvent the practical difficulties associated with the oestrous detection. Ovulation synchronization protocols, such as Ovsynch (Day 0 GnRH, Day 7 PGF2α, Day 9 GnRH, Day 10 timed artificial insemination – TAI; Pursley et al. 1995) and Cosynch (TAI performed at the same time as the second GnRH injection – Day 9; Rabaglino et al. 2010; Santos et al. 2010), are commonly used. Recently, reduction in the interval between the initial GnRH and PGF2α injections from Day 7 to Day 5 (Day 5 Cosynch programme) was shown to improve pregnancy rates in lactating dairy cows (Santos et al. 2010). The main limitation of these programmes is the reduced ability of PGF2α products to regress a newly formed CL, which may still be at the refractory stage. Therefore, a second PGF2α injection is often applied approximately 12 h after the first one. This represents additional animal handling and costs. Nonetheless, even with the second PGF2α injection, complete CL regression is not always achieved (p > 0.25 ng/ml), what impedes pregnancy rates. The abnormal release and function of cytokines and AA metabolites, as PGF2α and LPA, are pointed out as the main mechanisms inducing CL function disorders, including the inhibition of classical luteotrophic hormones as LH and equine chorionic gonadotropic. In fact, the appropriate expression of AA metabolizing enzymes is crucial for luteolysis induction. Thus, a subnormal CL will not prepare the uterus optimally for pregnancy establishment. An adequate P4 secretion needed for implantation and pregnancy progression will not be ensured and abortion will be the ultimate consequence (McMillan and Day 1982). Not only the administration of PGF2α or aPGF2α in cattle during luteal phase induces premature luteolysis, but also it may impair the process of follicular selection and new CL formation and future function (McCracken et al. 1999; Hansen et al. 1987; Skarzynski et al. 2009). Luteal P4 production was shown to be significantly lower in cows submitted to pharmacological synchronization of the oestrous cycle than those presenting spontaneous oestrous cycle. Similarly, the oestrous synchronization by double administration of aPGF2α resulted in lower luteal P4 secretion (Skarzynski et al. 2009). The oestrous synchronization, depending on the method and aPGF2α used, differentially modulates basal secretion of P4 by bovine CL and may decrease luteal sensitivity to luteotropic factors (LH and PGE2; Skarzynski et al. 2009). These results suggest that lower P4 secretion of and reduction in CL sensitivity to luteotropic factors may be a reason for luteal failure that can influence fertility and decrease pregnancy rates in cows. A better knowledge on the physiological status of the CL on Day 5–8 following pharmacological synchronization seems to be a crucial step to comprehend embryo implantation and development in cows. Moreover, the incomplete understanding of early CL refractoriness (Days 0–5) is a crucial scientific question to be answered in applied agriculture field. The ability of PGF2α to regress a newly formed CL remains a limitation to the oestrous synchronization programmes. Indeed, the underlying mechanisms associated with the stage-specific response to PGF2α are subject of intense research in recent years and are being revised and reshaped.


  1. Top of page
  2. Contents
  3. Introduction
  4. Regulation of Luteal Formation and Angiogenesis by Local Factors
  5. Conclusions and Practical Implications
  6. Funding
  7. Conflicts of interest
  8. Author Contributions
  9. References

Grant in Aid from National Research Center – Project OPUS, No DEC-2011/03/B/NZ9/01634 (Principal Investigators: Dr D.J. Skarzynski & Dr. R. Meidan). Karolina Lukasik was supported by the European Union within the European Social Fund (DrINNO).

Author Contributions

  1. Top of page
  2. Contents
  3. Introduction
  4. Regulation of Luteal Formation and Angiogenesis by Local Factors
  5. Conclusions and Practical Implications
  6. Funding
  7. Conflicts of interest
  8. Author Contributions
  9. References

All the authors contributed significantly in the elaboration of this manuscript. R. Meidan and D. Skarzynski serve equivocally as senior authors. The authors Olsztyn, D. Skarzynski, K. Peiotrowska-Tomala, K. Lukasik and A. Galvão were responsible for the initial elaboration of the chapters Cytokines, Phospholipids metabolites, Sex hormones, Death ligands, and Conclusions and practical implications. Authors Rehovot, S. Farberov, Y. Zalman, and R. Meidan, wrote the remaining chapters of the manuscript. A. Galvão corrected and improved the spelling and grammar.


  1. Top of page
  2. Contents
  3. Introduction
  4. Regulation of Luteal Formation and Angiogenesis by Local Factors
  5. Conclusions and Practical Implications
  6. Funding
  7. Conflicts of interest
  8. Author Contributions
  9. References
  • Acosta TJ, Bah MM, Korzekwa A, Woclawek-Potocka I, Markiewicz W, Jaroszewski JJ, Okuda K, Skarzynski DJ, 2009: Acute changes in circulating concentrations of progesterone and nitric oxide and partial pressure of oxygen during PGF2α-induced luteolysis in cattle. J Reprod Dev 55, 149155.
  • Al-Gubory KH, Ceballos-Picot I, Nicole A, 2005: Changes in activities of superoxide dismutase, nitric oxide synthase, glutathione-dependent enzymes and the incidence of apoptosis in sheep corpus luteum during the estrous cycle. Biochim Biophys Acta 10, 348357.
  • Alila HW, Corradino RA, Hansel W, 1988: A comparison of the effects of cyclooxygenase prostanoids on progesterone production by small and large bovine luteal cells. Prostaglandins 36, 259270.
  • Anderson LE, Schultz MK, Wiltbank MC, 1999: Prostaglandin moieties that determine receptor binding specificity in the bovine corpus luteum. J Reprod Fertil 116, 133141.
  • Anderson LE, Wu YL, Tsai SJ, Wiltbank MC, 2001: Prostaglandin F receptor in the corpus luteum: recent information on the gene, messenger ribonucleic acid, and protein. Biol Reprod 64, 10411047.
  • Antonsson B, 2001: Bax and other pro-apoptotic Bcl-2 family of “killer-proteins” and their victim, the mitochondrion. Cell Tissue Res 306, 347361.
  • Arosh JA, Banu SK, Chapdelaine P, Madore E, Sirois J, Fortier MA, 2004: Prostaglandin biosynthesis, transport, and signaling in corpus luteum: a basis for autoregulation of luteal function. Endocrinology 145, 25512560.
  • Atli MO, Bender RW, Mehta V, Bastos MR, Luo W, Vezina CM, Wiltbank MC, 2012: Patterns of gene expression in the bovine corpus luteum following repeated intrauterine infusions of low doses of prostaglandin F. Biol Reprod 86, 113.
  • Bah MM, Acosta TJ, Pilawski W, Deptula K, Okuda K, Skarzynski DJ, 2006: Role of intraluteal prostaglandin F, progesterone and oxytocin in basal and pulsatile progesterone release from developing bovine corpus luteum. Prostaglandins Other Lipid Mediat 79, 218229.
  • Bauer M, Reibiger I, Spanel-Borowski K, 2001: Leucocyte proliferation in the bovine corpus luteum. Reproduction 121, 297305.
  • Berisha B, Schams D, Kosmann M, Amselgruber W, Einspanier R, 2000: Expression and tissue concentration of vascular endothelial growth factor, its receptors, and localization in the bovine corpus luteum during estrous cycle and pregnancy. Biol Reprod 63, 11061114.
  • Berisha B, Meyer HH, Schams D, 2010: Effect of prostaglandin F2 alpha on local luteotropic and angiogenic factors during induced functional luteolysis in the bovine corpus luteum. Biol Reprod 82, 940947.
  • Blair RM, Saatman R, Liou SS, Fortune JE, Hansel W, 1997: Roles of leukotrienes in bovine corpus luteum regression: an in vivo microdialysis study. Proc Soc Exp Biol Med 216, 7280.
  • Bowolaksono A, Nishimura R, Hojo T, Sakumoto R, Acosta TJ, Okuda K, 2008: Anti-apoptotic roles of prostaglandin E2 and F2alpha in bovine luteal steroidogenic cells. Biol Reprod 79, 310317.
  • Carambula SF, Matikainen T, Lynch MP, Flavell RA, Dias Gonçalves PB, Tilly JL, Rueda BR, 2002: Caspase-3 is a pivotal mediator of apoptosis during regression of the ovarian corpus luteum. Endocrinology 143, 14951501.
  • Chen SU, Chou CH, Lee H, Ho CH, Lin CW, Yang YS, 2008: Lysophosphatidic acid up-regulates expression of interleukin-8 and -6 in granulosa-lutein cells through its receptors and nuclear factor-kappaB dependent pathways: implications for angiogenesis of corpus luteum and ovarian hyperstimulation syndrome. J Clin Endocrinol Metab 93, 935943.
  • Christenson LK, Stouffer RL, 1997: Follicle-stimulating hormone and luteinizing hormone/chorionic gonadotropin stimulation of vascular endothelial growth factor production by macaque granulosa cells from pre- and periovulatory follicles. J Clin Endocrinol Metab 82, 21352142.
  • Davis JS, Rueda BR, 2002: The corpus luteum: an ovarian structure with maternal instincts and suicidal tendencies. Front Biosci 7, 19491978.
  • Davis JS, Rueda BR, Spanel-Borowski K, 2003: Microvascular endothelial cells of the corpus luteum. Reprod Biol Endocrinol 10, 89.
  • Doerr MD, Goravanahally MP, Rhinehart JD, Inskeep EK, Flores JA, 2008: Effects of endothelin receptor type-A and type-B antagonists on prostaglandin F2alpha-induced luteolysis of the sheep corpus luteum. Biol Reprod 78, 688696.
  • Ferrara N, Davis-Smyth T, 1997: The biology of vascular endothelial growth factor. Endocr Rev 18, 425.
  • Fraser HM, Morris KD, Wiegand SJ, Wilson H, 2010: Inhibition of vascular endothelial growth factor during the postovulatory period prevents pregnancy in the marmoset. Contraception 82, 572578.
  • Friedman A, Weiss S, Levy N, Meidan R, 2000: Role of tumor necrosis factor alpha and its type I receptor in luteal regression: induction of programmed cell death in bovine corpus luteum-derived endothelial cells. Biol Reprod 63, 19051912.
  • Galvão A, Skarzynski DJ, Szostek AZ, Ramilo D, Tramontano A, Mollo A, Mateus L, Ferreira-Dias G, 2012a: The cytokines Tumor necrosis factor-α and Interferon-γ participate in the regulation of the equine corpus luteum as auto-, paracrine factors. J Reprod Immunol 93, 2837.
  • Galvão A, Henriques S, Pestka D, Lukasik K, Skarzynski D, Mateus LM, Ferreira-Dias GM, 2012b: Equine luteal function regulation may depend on the interaction between cytokines and vascular endothelial growth factor: an in vitro study. Biol Reprod 86, 187.
  • Girsh E, Greber Y, Meidan R, 1995: Luteotrophic and luteolytic interactions between bovine small and large luteal-like cells and endothelial cells. Biol Reprod 52, 954962.
  • Gospodarowicz D, Cheng J, Lui GM, Baird A, Esch F, Bohlen P, 1985: Corpus luteum angiogenic factor is related to fibroblast growth factor. Endocrinology 117, 23832391.
  • Grazul-Bilska AT, Redmer DA, Jablonka-Shariff A, Biondini ME, Reynolds LP, 1995: Proliferation and progesterone production of ovine luteal cells from several stages of the estrous cycle: effects of fibroblast growth factors and luteinizing hormone. Can J Physiol Pharmacol 73, 491500.
  • Gross A, Yin XM, Wang K, Wei MC, Jockel J, Milliman C, Erdjument-Bromage H, Tempst P, Korsmeyer SJ, 1999: Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-XL prevents this release but not tumor necrosis factor-R1/Fas death. J Biol Chem 274, 11561163.
  • Hansel W, 1996: Special topics in theriogenology, no 2: the bovine corpus luteum. Theriogenology 45, 12651428.
  • Hansen TR, Randel RD, Segerson EC Jr, Rutter LM, Harms PG, 1987: Corpus luteum function following spontaneous or PGF-induced estrus in Brahman cows and heifers. J Anim Sci 65, 524533.
  • Hewitson KS, Schofield CJ, Ratcliffe PJ, 2007: Hypoxia-inducible factor prolyl-hydroxylase: purification and assays of PHD2. Methods Enzymol 435, 2542.
  • Hojo T, Oda A, Lee SH, Acosta TJ, Okuda K, 2010: Effects of tumor necrosis factor α and interferon c on the viability and mRNA expression of TNF receptor type I in endothelial cells from the bovine corpus luteum. J Reprod Dev 56, 515519.
  • Inoue A, Yanagisawa M, Kimura S, Kasuya Y, Miyauchi T, Goto K, Masaki T, 1989: The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci U S A 86, 28632867.
  • Jaroszewski JJ, Hansel W, 2000: Intraluteal administration of a nitric oxide synthase blocker stimulates progesterone and oxytocin secretion and prolongs the life span of the bovine corpus luteum. Proc Soc Exp Biol Med 224, 5055.
  • Jee BC, Kim SH, Moon SY, 2003: The role of nitric oxide on apoptosis in human luteinized granulosa cells. Immunocytochemical evidence. Gynecol Obstet Invest 56, 143147.
  • Jiang YF, Tsui KH, Wang PH, Lin CW, Wang JY, Hsu MC, Chen YC, Chiu CH, 2011: Hypoxia regulates cell proliferation and steroidogenesis through protein kinase A signaling in bovine corpus luteum. Anim Reprod Sci 129, 152161.
  • Kim MR, Choi HS, Heo TH, Hwang SW, Kang KW, 2008: Induction of vascular endothelial growth factor by peptidyl-prolyl isomerase Pin1 in breast cancer cells. Biochem Biophys Res Commun 369, 547553.
  • Kim J, Bagchi IC, Bagchi MK, 2009: Signaling by hypoxia-inducible factors is critical for ovulation in mice. Endocrinology 150, 33923400.
  • Klipper E, Levit A, Mastich Y, Berisha B, Schams D, Meidan R, 2010: Induction of endothelin-2 expression by luteinizing hormone and hypoxia: possible role in bovine corpus luteum formation. Endocrinology 151, 19141922.
  • Ko C, Gieske MC, Al-Alem L, Hahn Y, Su W, Gong MC, Iglarz M, Koo Y, 2006: Endothelin-2 in ovarian follicle rupture. Endocrinology 147, 17701779.
  • Kobayashi S, Berisha B, Amselgruber WM, Schams D, Miyamoto A, 2001: Production and localization of angiotensin II in the bovine early corpus luteum: a possible interaction with luteal angiogenic factors and prostaglandin F2. J Endocrinol 170, 369380.
  • Kobayashi S, Acosta TJ, Hayashi K, Berisha B, Ozawa T, Ohtani M, Schams D, Miyamoto A, 2002: Intraluteal release of prostaglandin F2 and E2 during corpora lutea development in the cow. J Reprod Dev 48, 583590.
  • Korzekwa AJ, Jaroszewski JJ, Bogacki M, Deptula KM, Maslanka TS, Acosta TJ, Okuda K, Skarzynski DJ, 2004: Effects of prostaglandin F and nitric oxide on the secretory function of bovine luteal cells. J Reprod Dev 50, 411417.
  • Korzekwa AJ, Shuko M, Jaroszewski J, Wocławek-Potocka I, Okuda K, Skarzynski DJ, 2006: Nitric oxide induces programmed cell dead in the bovine corpus luteum: mechanism of action. J Reprod Dev 52, 353361.
  • Korzekwa AJ, Murakami S, Wocławek-Potocka I, Bah MM, Okuda K, Skarzynski DJ, 2008a: The influence of tumor necrosis factor α (TNF) on the secretory function of bovine corpus luteum: TNF and its receptors expression during the estrous cycle. Reprod Biol 8, 245262.
  • Korzekwa AJ, Jaroszewski JJ, Woclawek-Potocka I, Bah MM, Skarzynski DJ, 2008b: Luteolytic effect of prostaglandin F on bovine corpus luteum depends on cell composition and contact. Reprod Domest Anim 43, 464472.
  • Korzekwa AJ, Bah MM, Kurzynowski A, Lukasik K, Groblewska A, Skarzynski DJ, 2010a: Leukotrienes modulate secretion of P4 and prostaglandins during the estrous cycle and early pregnancy in cattle: an in vivo study. Reproduction 140, 767776.
  • Korzekwa AJ, Lukasik K, Skarzynski DJ, 2010b: Leukotrienes are auto-/paracrine factors in the bovine corpus luteum: an in vitro study. Reprod Domest Anim 45, 10891097.
  • Korzekwa AJ, Bodek G, Bukowska J, Blitek A, Skarzynski DJ, 2011: Characterization of bovine immortalized luteal endothelial cells: action of cytokines on production and content of arachidonic acid metabolites. Reprod Biol Endocrinol 9, 2735.
  • Kotwica J, Skarzynski DJ, Mlynarczuk J, Rekawiecki R, 2003: Role of prostaglandin E2 in basal and noradrenaline-induced progesterone secretion by the bovine corpus luteum. Prostaglandins Other Lipid Mediat 70, 351359.
  • Kotwica J, Rekawiecki R, Duras M, 2004: Stimulatory influence of progesterone on its own synthesis in bovine corpus luteum. Bull Vet Inst Pulawy 48, 139145.
  • Kou R, Igarashi J, Michel T, 2002: Lysophosphatidic acid and receptor-mediated activation of endothelial nitric-oxide synthase. Biochemistry 41, 49824988.
  • Kowalczyk-Zieba I, Boruszewska D, Saulnier-Blache JS, Lopes Da Costa L, Jankowska K, Skarzynski DJ, Woclawek-Potocka I, 2012a: Lysophosphatidic acid action in the bovine corpus luteum -an in vitro study. J Reprod Dev 58, 661671.
  • Kowalczyk-Zieba I, Boruszewska D, Skarzynski DJ, Woclawek-Potocka I, 2012b: Lyspohosphatidic acid can inhibit nitric oxide action during functional and structural regression of the bovine corpus luteum. Repord Domest Anim 47, 32.
  • Lee S, Acosta TJ, Nakagawa Y, Okuda K, 2010: Role of nitric oxide in the regulation of superoxide dismutase and prostaglandin F(2alpha) production in bovine luteal endothelial cells. J Reprod Dev 56, 454459.
  • Levy N, Kobayashi S, Roth Z, Wolfenson D, Miyamoto A, Meidan R, 2006: Administration of prostaglandin F2α during the early bovine luteal phase does not alter the expression of ET-1 and of its type A receptor: a possible cause for corpus luteum refractoriness. Biol Reprod 3, 377382.
  • Mamluk R, Defer N, Hanoune J, Meidan R, 1999: Molecular identification of adenylyl cyclase 3 in bovine corpus luteum and its regulation by prostaglandin F2-induced signaling pathways. Endocrinology 140, 46014608.
  • McCracken JA, Custer EE, Lamsa JC, 1999: Luteolysis: a neuroendocrine-mediated event. Physiol Rev 79, 263323.
  • McMillan KL, Day AM, 1982: Prostaglandin F2α-fertility drug in dairy cattle. Theriogenology 16, 245253.
  • Meidan R, Levy N, 2002: Endothelin-1 receptors and biosynthesis in the corpus luteum: molecular and physiological implications. Domest Anim Endocrinol 23, 287298.
  • Meidan R, Levy N, 2007: The ovarian endothelin network: an evolving story. Trends Endocrinol Metab 18, 379385.
  • Meidan R, Milvae RA, Weiss S, Levy N, Friedman A, 1999: Intraovarian regulation of luteolysis. J Reprod Fertil Suppl 54, 217228.
  • Meidan R, Levy N, Kisliouk T, Podlovny L, Rusiansky M, Klipper E, 2005: The yin and yang of corpus luteum-derived endothelial cells: balancing life and death. Domest Anim Endocrinol 29, 318328.
  • Milvae RA, Hansel W, 1983: Prostacyclin, prostaglandin F2 and progesterone production by bovine luteal cells during the estrous cycle. Biol Reprod 29, 10631068.
  • Miyamoto A, von Lutzow H, Schams D, 1993: Acute actions of prostaglandin F2, E2, and I2 in microdialyzed bovine corpus luteum in vitro. Biol Reprod 49, 423430.
  • Mondal M, Schilling B, Folger J, Steibel JP, Buchnick H, Zalman Y, Ireland JJ, Meidan R, Smith GW, 2011: Deciphering the luteal transcriptome: potential mechanisms mediating stage-specific luteolytic response of the corpus luteum to prostaglandin F. Physiol Genomics 43, 447456.
  • Neuvians TP, Schams D, Berisha B, Pfaffl MW, 2004: Involvement of pro-inflammatory cytokines, mediators of inflammation, and basic fibroblast growth factor in prostaglandin F2-induced luteolysis in bovine corpus luteum. Biol Reprod 70, 473480.
  • Nishimura R, Bowolaksono A, Acosta TJ, Murakami S, Piotrowska KK, Skarżyński DJ, Okuda K, 2004: Possible role of interleukin-1 in the regulation of bovine corpus luteum throughout the luteal phase. Biol Reprod 71, 81693.
  • Niswender GD, Juengel JL, Silva PJ, Rollyson MK, McIntush EW, 2000: Mechanisms controlling the function and life span of the corpus luteum. Physiol Rev 80, 129.
  • Ohtani M, Takase S, Wijayagunawardane MP, Tetsuka M, Miyamoto A, 2004: Local interaction of prostaglandin F 2alpha with endothelin-1 and tumor necrosis factor-alpha on the release of progesterone and oxytocin in ovine corpora lutea in vivo: a possible implication for a luteolytic cascade. Reproduction 127, 117124.
  • Okuda K, Sakumoto R, 2003: Multiple roles of TNF super family members in corpus luteum function. Reprod Biol Endocrinol 10, 195.
  • Okuda K, Sakumoto R, Uenoyama Y, Berisha B, Miyamoto A, Schams D, 1999: Tumor necrosis factor alpha receptors in microvascular endothelial cells from bovine corpus luteum. Biol Reprod 61, 10171022.
  • Okuda K, Miyamoto Y, Skarzynski DJ, 2002: Regulation of endometrial prostaglandin F synthesis during luteolysis and early pregnancy in cattle. Domest Anim Endocrinol 23, 255264.
  • Okuda K, Korzekwa A, Shibaya M, Murakami S, Nishimura R, Tsubouchi M, Woclawek-Potocka I, Skarzynski DJ, 2004: Progesterone is a suppressor of apoptosis in bovine luteal cells. Biol Reprod 71, 20652071.
  • Ornitz DM, Itoh N, 2001: Fibroblast growth factors. Genome Biol 2, reviews 3005.13005.12.
  • Orrenius S, McCabe MJ Jr, Nicotera P, 1992: Ca(2+)-dependent mechanisms of cytotoxicity and programmed cell death. Toxicol Lett 64, 357364.
  • Palanisamy GS, Cheon YP, Kim J, Kannan A, Li Q, Sato M, Mantena SR, Sitruk-Ware RL, Bagchi MK, Bagchi IC, 2006: A novel pathway involving progesterone receptor, endothelin-2, and endothelin receptor B controls ovulation in mice. Mol Endocrinol 20, 27842795.
  • Panetti TS, Chen H, Misenheimer TM, Getzler SB, Mosher DF, 1997: Endothelial cell mitogenesis induced by LPA: inhibition by thrombospondin-1 and thrombospondin-2. J Lab Clin Med 129, 208216.
  • Pate JL, 1995: Involvement of immune cells in regulation of ovarian function. J Reprod Fertil 49, 365377.
  • Pate JL, 2003: Lives in the balance: responsiveness of the corpus luteum to uterine and embryonic signals. Reproduction 61, 207217.
  • Pate JL, Keyes PL, 2001: Immune cells in the corpus luteum: friends or foes? Reproduction 122, 665676.
  • Pate JL, Johnson-Larson CJ, Ottobre JS, 2012: Life or death decisions in the Corpus Luteum. Reprod Domest Anim 47, 297303.
  • Penny LA, Armstrong D, Bramley TA, Webb R, Collins RA, Watson ED, 1999: Immune cells and cytokine production in the bovine corpus luteum throughout the oestrous cycle and after induced luteolysis. J Reprod Fertil 115, 8796.
  • Petroff MG, Petroff BK, Pate JL, 1999: Expression of cytokine messenger ribonucleic acid in the bovine corpus luteum. Endocrinology 140, 10181021.
  • Petroff MG, Petroff BK, Pate JL, 2001: Mechanisms of cytokine-induced death of cultured bovine luteal cells. Reproduction 121, 753760.
  • Preutthipan S, Chen SH, Tilly JL, Kugu K, Lareu RR, Dharmarajan AM, 2004: Inhibition of nitric oxide synthesis potentiates apoptosis in the rabbit corpus luteum. Reprod Biomed Online 9, 264270.
  • Pursley JR, Mee MO, Wiltbank MC, 1995: Synchronization of ovulation in dairy cows using PGF2 and GnRH. Theriogenology 44, 915923.
  • Rabaglino MB, Risco CA, Thatcher MJ, Kim IH, Santos JE, Thatcher WW, 2010: Application of one injection of prostaglandin F(2alpha) in the five-day Co-Synch+CIDR protocol for estrous synchronization and resynchronization of dairy heifers. J Dairy Sci 93, 10501058.
  • Rao CV, 1974: Differential properties of prostaglandin and gonadotropin receptors in the bovine corpus lutuem cell membranes. Prostaglandins 6, 313328.
  • Rekawiecki R, Kowalik MK, Slonina D, Kotwica J, 2008: Regulation of progesterone synthesis and action in bovine corpus luteum. J Physiol Pharmacol 59, 7589.
  • Reynolds LP, Ford SP, 1984: Contractility of the ovarian vascularbed during the oestrous cycle and early pregnancy in gilts. J Reprod Fertil 71, 6571.
  • Robinson RS, Nicklin LT, Hammond AJ, Schams D, Hunter MG, Mann GE, 2007: Fibroblast growth factor 2 is more dynamic than vascular endothelial growth factor A during the follicle-luteal transition in the cow. Biol Reprod 77, 2836.
  • Rueda BR, Hendry IR, Hendry WJ III, Fong HW, Stormashak F, Slaydenlayden OD, Davis JS, 2000: Decreased progesterone level and progesterone receptors antagonists promote apoptotic cell death in bovine luteal cells. Biol Reprod 62, 269276.
  • Sakumoto R, Okuda K, 2003: Multiple roles of TNF super family members in corpus luteum function. Reprod Biol Endocrinol 1, 95.
  • Sakumoto R, Berisha B, Kawate N, Schams D, Okuda K, 2000: Tumor necrosis factor and its receptors in bovine corpus luteum throughout the estrous cycle. Biol Reprod 62, 192199.
  • Sakumoto R, Vermehren M, Kenngott RA, Okuda K, Sinowatz F, 2010: Changes in the levels of progesterone receptor mRNA and protein in the bovine corpus luteum during the estrous cycle. J Reprod Dev 56, 219222.
  • Sakumoto R, Vermehren M, Kenngott RA, Okuda K, Sinowatz F, 2011: Localization of gene and protein expressions of tumor necrosis factor-α and tumor necrosis factor receptor types I and II in the bovine corpus luteum during the estrous cycle. J Anim Sci 89, 30403047.
  • Sangsritavong S, Combs DK, Sartori R, Armentano LE, Wiltbank MC, 2002: High feed intake increases liver blood flow and metabolism of progesterone and estradiol-17beta in dairy cattle. J Dairy Sci 85, 28312842.
  • Santos JE, Narciso CD, Rivera F, Thatcher WW, Chebel RC, 2010: Effect of reducing the period of follicle dominance in a timed artificial insemination protocol on reproduction of dairy cows. J Dairy Sci 93, 29762988.
  • Sawyer HR, Niswender KD, Braden TD, Niswender GD, 1990: Nuclear changes in ovine luteal cells in response to PGF2a. Domest Anim Endocrinol 7, 229237.
  • Schams D, Berisha B, 2004: Regulation of CL function in cattle-an overview. Reprod Domest Anim 39, 241251.
  • Shaw DW, Britt JH, 1995: Concentrations of tumor necrosis factor alpha and progesterone within the bovine corpus luteum sampled by continuous-flow microdialysis during luteolysis in vivo. Biol Reprod 53, 847854.
  • Shirasuna K, Asaoka H, Acosta TJ, Wijayagunawardane MP, Matsui M, Ohtani M, Miyamoto A, 2004: Endothelin-1 within the corpus luteum during spontaneous luteolysis in the cow: local interaction with prostaglandin F2 and angiotensin II. J Cardiovasc Pharmacol 44, S252S255.
  • Shirasuna K, Watanabe S, Asahi T, Wijayagunawardane MP, Sasahara K, Jiang C, Matsui M, Sasaki M, Shimizu T, Davis JS, Miyamoto A, 2008: Prostaglandin F increases endothelial nitric oxide synthase in the periphery of the bovine corpus luteum: the possible regulation of blood flow at an early stage of luteolysis. Reproduction 135, 527539.
  • Shirasuna K, Nitta A, Sineenard J, Shimizu T, Bollwein H, Miyamoto A, 2012a: Vascular and immune regulation of corpus luteum development, maintenance, and regression in the cow. Domest Anim Endocrinol 43, 198211.
  • Shirasuna K, Akabane Y, Beindorff N, Nagai K, Sasaki M, Shimizu T, Bollwein H, Meidan R, Miyamoto A, 2012b: Expression of prostaglandin F (PGF) receptor and its isoforms in the bovine corpus luteum during the estrous cycle and PGF-induced luteolysis. Domest Anim Endocrinol 43, 227238.
  • Skarzynski DJ, Okuda K, 1999: Sensitivity of bovine corpora lutea to prostaglandin F is dependent on progesterone, oxytocin, and prostaglandins. Biol Reprod 60, 12921298.
  • Skarzynski DJ, Okuda K, 2010: Inter- and intra-cellular mechanisms of prostaglandin F action during corpus luteum regression in cattle. Soc Reprod Fertil Suppl 67, 305324.
  • Skarzynski DJ, Bah MM, Deptula KM, Woclawek-Potocka I, Korzekwa A, Shibaya M, Pilawski W, Okuda K, 2003a: Roles of tumor necrosis factor-alpha of the estrous cycle in cattle: an in vivo study. Biol Reprod 69, 19071913.
  • Skarzynski DJ, Jaroszewski JJ, Bah MM, Deptuła KM, Barszczewska B, Gawronska B, Hansel W, 2003b: Administration of a nitric oxide synthase inhibitor counteracts prostaglandin F2α-induced luteolysis in cattle. Biol Reprod 68, 16741681.
  • Skarzynski DJ, Jaroszewski JJ, Okuda K, 2005: Role of tumor necrosis factor-alpha and nitric oxide in luteolysis in cattle. Domest Anim Endocrinol 29, 340346.
  • Skarzynski DJ, Piotrowska K, Bah MM, Korzekwa A, Woclawek-Potocka I, Sawai K, Okuda K, 2007: Effects of tumor necrosis factor (TNF) on the secretory function of the bovine reproductive tract depend on TNF achieved concentrations. Reprod Domest Anim 44, 371379.
  • Skarzynski DJ, Siemieniuch M, Pilawski W, Woclawek-Potocka I, Bah MM, Majewska M, Jaroszewski JJ, 2009: In vitro assessment of progesterone and prostaglandin E2 production by the corpus luteum in cattle following pharmacological synchronization of the estrus. J Reprod Dev 55, 170176.
  • Spencer TE, Johnson GA, Bazer FW, Burghardt RC, Palmarini M, 2007: Pregnancy recognition and conceptus implantation in domestic ruminants: roles of progesterone, interferons and endogenous retroviruses. Reprod Fertil Dev 19, 6578.
  • Sugino N, Suzuki T, Sakata A, Miwa I, Asada H, Taketani T, Yamagata Y, Tamura H, 2005: Angiogenesis in the human corpus luteum: changes in expression of angiopoietins in the corpus luteum throughout the menstrual cycle and in early pregnancy. J Clin Endocrinol Metab 90, 61416148.
  • Szostek AZ, Lukasik K, Majewska M, Bah MM, Znaniecki R, Okuda K, Skarzynski DJ, 2011: Tumor necrosis factor-α inhibits luteinizing hormone- and prostaglandin E2-stimulated progesterone secretion by the bovine corpus luteum. Domest Anim Endocrinol 40, 183191.
  • Tanaka J, Acosta TJ, Berisha B, Tetsuka M, Matsui M, Kobayashi S, Schams D, Miyamoto A, 2004: Relative changes in mRNA expression of angiopoietins and receptors tie in bovine corpus luteum during estrous cycle and prostaglandin F2alpha-induced luteolysis: a possible mechanism for the initiation of luteal regression. J Reprod Dev 50, 619626.
  • Taniguchi H, Yokomizo Y, Okuda K, 2002: Fas-fas ligand system mediates luteal cell death in bovine corpus luteum. Biol Reprod 66, 754759.
  • Terranova PF, 1997: Potential roles of tumor necrosis factor-alpha in follicular development, ovulation, and the life span of the corpus luteum. Domest Anim Endocrinol 14, 115.
  • Tesone M, Stouffer RL, Borman SM, Hennebold JD, Molskness TA, 2005: Vascular endothelial growth factor (VEGF) production by the monkey corpus luteum during the menstrual cycle: isoform-selective messenger RNA expression in vivo and hypoxia-regulated protein secretion in vitro. Biol Reprod 73, 927934.
  • Thatcher WW, Bilby TR, Bartolome JA, Silvestre F, Staples CR, Santos JE, 2006: Strategies for improving fertility in the modern dairy cow. Theriogenology 65, 3044.
  • Tilly JL, 1996: Apoptosis and ovarian function. Rev Reprod 1, 162172.
  • Townson DH, Liptak AR, 2003: Chemokines in the corpus luteum: implications of leukocyte chemotaxis. Reprod Biol Endocrinol 1, 94.
  • Townson DH, O'Connor CL, Pru JK, 2002: Expression of monocyte chemoattractant protein-1 and distribution of immune cell populations in the bovine corpus luteum throughout the estrous cycle. Biol Reprod 66, 361366.
  • Tsai SJ, Wiltbank MC, 1998: Prostaglandin F regulates distinct physiological changes in early and mid-cycle bovine corpora lutea. Biol Reprod 58, 346352.
  • Tsai SJ, Wiltbank MC, Bodensteiner KJ, 1996: Distinct mechanisms regulate induction of messenger ribonucleic acid for prostaglandin (PG) G/H synthase-2, PGE (EP3) receptor, and PGF2 alpha receptor in bovine preovulatory follicles. Endocrinology 137, 33483355.
  • Watanabe S, Shirasuna K, Matsui M, Yamamoto D, Berisha B, Schams D, Miyamoto A, 2006: Effect of intraluteal injection of endothelin type A receptor antagonist on PGF2alpha-induced luteolysis in the cow. J Reprod Dev 52, 551559.
  • Wiltbank MC, Dysko RC, Gallagher KP, Keyes PL, 1988: Relationship between blood flow and steroidogenesis in the rabbit corpus luteum. J Reprod Fertil 84, 513520.
  • Woad KJ, Hammond AJ, Hunter M, Mann GE, Hunter MG, Robinson RS, 2009: FGF2 is crucial for the development of bovine luteal endothelial networks in vitro. Reproduction 138, 581588.
  • Woad KJ, Hunter MG, Mann GE, Laird M, Hammond AJ, Robinson RS, 2012: Fibroblast growth factor 2 is a key determinant of vascular sprouting during bovine luteal angiogenesis. Reproduction 143, 3543.
  • Woclawek-Potocka I, Kondraciuk K, Skarzynski DJ, 2009: Lysophosphatidic acid stimulates prostaglandin E production in cultured stromal endometrial cells through LPA1 receptor. Exp Biol Med (Maywood) 234, 986993.
  • Woclawek-Potocka I, Kowalczyk-Zieba I, Skarzynski DJ, 2010: Lysophosphatidic acid action during early pregnancy in the cow: in vivo and in vitro studies. J Reprod Dev 56, 411420.
  • Wulff C, Wiegand SJ, Saunders PT, Scobie GA, Fraser HM, 2001: Angiogenesis during follicular development in the primate and its inhibition by treatment with truncated Flt-1-Fc (vascular endothelial growth factor Trap(A40). Endocrinology, 142, 32443254.
  • Yadav VK, Sudhagar RR, Medhamurthy R, 2002: Apoptosis during spontaneous and prostaglandin F-induced luteal regression in the buffalo cow (Bubalus bubalis): involvement of mitogen-activated protein kinases. Biol Reprod 67, 752759.
  • Yamashita H, Kamada D, Shirasuna K, Matsui M, Shimizu T, Kida K, Berisha B, Schams D, Miyamoto A, 2008: Effect of local neutralization of basic fibroblast growth factor or vascular endothelial growth factor by a specific antibody on the development of the corpus luteum in the cow. Mol Reprod Dev 75, 14491456.
  • Yoshioka S, Acosta TJ, Okuda K, 2012: Roles of cytokines and progesterone in the regulation of the nitric oxide generating system in bovine luteal endothelial cells. Mol Reprod Dev 79, 689696.
  • Zalman Y, Klipper E, Farberov S, Mondal M, Wee G, Folger JK, Smith GW, Meidan R, 2012: Regulation of angiogenesis-related prostaglandin F2alpha-induced genes in the bovine corpus luteum. Biol Reprod 86, 92.
  • Zipser RD, Laffi L, 1985: Prostaglandins, thromboxanes and leukotrienes in clinical medicine. West J Med 143, 485497.