Reproduction in Domestic Animals

58 DJ Skarzynski, G Ferreira-Dias and K Okuda(+)Prostaglandins(PGE 2, PGI 2, PGF 2a )LH/gonadotropins(+)P4Endothelial/luteal cellsdifferentiation and/orproliferationautocrine and ⁄ or paracrine factors, seem to be PGs andother arachidonic acid metabolites [PGE 2 , PGF 2a ,leucotrienes (LT)], neuropeptides [noradrenaline (NA)],peptide hormones [i.e. oxytocin (OT)], NO, growthfactors and hormones [vascular endothelial growthfactor (VEGF), fibroblastic growth factors (FGF),epidermal growth factor (EGF), growth hormone(GH), prolactin (PRL)] and steroids [P4 and 17boestradiol(E 2 )].Corpus luteum developmentThe physiological processes of CL growth and formationmight be regulated by many different factors, stillnot completely understood (Fig. 1) (Reynolds andRedmer 1999; Acosta and Miyamoto 2004; Schamsand Berisha 2004; Meidan et al. 2005; Ferreira-Dias andSkarzynski 2008). After ovulation, as the CL formsfrom the wall of the ruptured follicle, it grows andvascularizes rapidly. In fact, the rates of tissue growthand angiogenesis in the CL rival those of even thefastest growing tumours. The CL is a complex tissuecomposed of paranchymal (small and large steroidogenic)and non-parenchymal (fibroblast, vascularsmooth muscle, pericytes and endothelial) cells (Reynoldsand Redmer 1999; Lei et al. 2000; Towson et al.2002). In agreement with data from other tissues,VEGF seem to be a major angiogenic factor responsiblefor vascularization of the developing CL. Recent datasuggest that luteal expression of VEGF occurs primarilyin steroidogenic cells (granulose-lutein cells) and less inendothelial cells (specific perivascular cells, includingarteriolar smooth muscle and capillary pericytes), and isregulated primarily by oxygen levels (Berisha andSchams 2005; Ferreira-Dias and Skarzynski 2008).Soon after ovulation, pericytes derived from the thecalcompartment appear to be the first vascular cells toinvade the developing luteal parenchyma. The granulosa-derivedcells produce a factor that stimulatespericytes migration. Moreover, NO, which is a potentvasodilator and stimulates VEGF production andangiogenesis, is produced by endothelial cells of lutealarterioles and capillaries, often in association withexpression of VEGF by luteal perivascular cells (Berishaand Schams 2005).(+)Growth factors, cytokines(VEGF, FGF, IGF, EGF,TNFa)Fig. 1. Hypothetical model of the regulation of the CL development(see text for the details; adapted from Ferreira-Dias and Skarzynski2008)Basic FGF mRNA and protein and its receptors arepresent in the CL and may stimulate proliferation ofluteal endothelial cells (Reynolds and Redmer 1999;Berisha and Schams 2005). The IGF system plays a rolein CL development and may indirectly affect angiogenesisin the early CL by stimulating VEGF production(Schams and Berisha 2004; Berisha and Schams 2005).Thus, several growth factors act as auto-paracrineregulators affecting proliferation and differentiation ofthe developing CL cells (Reynolds and Redmer 1999;Acosta and Miyamoto 2004; Berisha and Schams 2005).Moreover, the luteotropic paracrine and ⁄ or autocrineeffects of OT, NO, PGF 2a and other metabolites ofarachidonic acid (PGE 2 , PGI 2 , leucotrienes) suggest thateikosanoids assume different and perhaps opposingroles depending on the cellular and hormonal milieu(Skarzynski et al. 2000, 2001; Weems et al. 2004; Meidanet al. 2005). Prostaglandins and leucotrienes mayregulate cell proliferation and stimulate P4 productionregulating ⁄ stimulating CL development and formation.Just after ovulation, the basement membrane breaksdown, and blood vessels from the theca interna invadethe avascular granulose-lutein cell layers (Acosta andMiyamoto 2004; Berisha and Schams 2005). Thesephenomena are thought to occur under hypoxic conditions.Thus, we have proposed a model for the initialprocess of luteal vascularization in which hypoxia playsa major role. In this model, a paracrine loop existsbetween the vascular endothelial cells which produceNO, and granulose-lutein cells which mainly produceVEGF, to ensure coordinated regulation of lutealvasodilation and angiogenesis. During this decade,hypoxia-inducible factor 1 (HIF1) has been recognizedto have critical roles in angiogenesis via transcriptionalregulation of angiogenic factors, such as VEGF. Ourrecent study indicates that HIF1 is essential for theVEGF-induced angiogenesis during luteal development,and suggests that formation of luteal vasculature incows is regulated by hypoxic condition following folliclerupture (Nishimura R and Okuda K, unpublished data).Maintenance of the corpus luteum: mandatory role ofprogesteroneIn cows, LH and GH are the primary hormones whichsupport the development and function of the CL (Hanseland Dowd 1986; Niswender et al. 2007). However, thelocal angiogenic growth factors (VEGD, EGF, FGF),PGs and peptide hormones (OT) should be considerednot only the potent regulators of luteal development, butalso important factors regulating P4 secretion andlifespan of CL (Skarzynski et al. 2001; Berisha andSchams 2005; Meidan et al. 2005; Fig. 1). Moreover, P4also has an effect on function of the bovine early and midCL in an autocrine and paracrine fashion (Skarzynskiand Okuda 1999; Duras et al. 2005). In order to removethe influence of P4 produced by cultured bovine lutealcells, we treated cells with a specific P4 antagonist(onapristone; Skarzynski and Okuda 1999; Okuda et al.2004). In early luteal cells, secretions of P4 OT, PGF 2aand PGE 2 were reduced by onapristone. Moreover, theP4 antagonist inhibited OT secretion by mid-cycle lutealcells, although it stimulated PGF 2a secretion (SkarzynskiÓ 2008 The Authors. Journal compilation Ó 2008 Blackwell Verlag