Angiogenesis in the human corpus luteum: simulated early pregnancy by HCG treatment is associated with both angiogenesis and vessel stabilization

Anoestrous ewes can be induced to ovulate by the socio-sexual, 'ram effect'. However, in some ewes, the induced ovulation is followed by an abnormally short luteal phase causing a so-called 'short cycle'. The defect responsible for this luteal dysfunction has not been identified. In this study, we investigated ovarian and uterine factors implicated in male-induced short cycles in anoestrous ewes using a combined endocrine and molecular strategy. Before ovulation, we were able to detect a moderate loss of thecal expression of steroid acute regulatory protein (STAR) in ewes that had not received progesterone priming (which prevents short cycles). At and following ovulation, we were able to identify a significant loss of expression of genes coding key proteins involved in the biosynthesis of progesterone (STAR, CYP11A1 and HSD3B1 (HSD3B)) as well as genes coding proteins critical for vascular development during early luteal development (VEGFA and KDR (VEGFR2)), suggesting dysfunction in at least two pathways critical for normal luteal function. Furthermore, these changes were associated with a significant reduction of progesterone production and luteal weight. Additionally, we cast doubt on the proposed uterus-mediated effect of prostaglandin F2a (PGF2a) as a cause of short cycles by demonstrating the dysregulation of luteal expression of the PGF receptor, which mediates the luteal effects of PGF2a, and by finding no significant changes in the circulating concentrations of PGFM, the principal metabolite of PGF2a in ewes with short cycles. This study is the first of its kind to examine concurrently the endocrine and molecular events in the follicular and early luteal stages of the short cycle. Free French abstractA French translation of this abstract is freely available at

Section: Discussionmentioning

confidence: 99%

Short oestrous cycles in sheep during anoestrus involve defects in progesterone biosynthesis and luteal neovascularisation

Brown

Nys²,

Cognié³

et al. 2014

“…In simulated early pregnancy, human chorionic gonadotrophin (hCG) has effects on immune cells, endothelial cells and fibroblasts (Duncan et al 1998a, 1998b, Duncan 2000, Wulff et al 2001) which do not express LH/hCG receptors (LHCGR). Therefore, if paracrine molecules, which are regulated by hCG, are involved in luteolysis, these molecules should be the products of steroidogenic cells and have receptors on target cells.…”

Section: Introductionmentioning

confidence: 99%

Expression and regulation of oestrogen receptors in the human corpus luteum

Driesche¹,

Smith²,

Myers³

et al. 2008

The molecular mechanisms underlying the control of corpus luteum lifespan in women are not fully understood. Oestradiol has various luteolytic, or luteotrophic, functions in some species, and as it is synthesised within the human corpus luteum, it is an excellent candidate molecule to be a paracrine regulator of luteal function. This study aimed to comprehensively investigate the expression, regulation and effects of oestrogen receptors (ER) in human luteal cells. Genomic oestrogen receptors ERa, ERb1 and ERb2 were immunolocalised in human corpora lutea from throughout the luteal phase. mRNA expression was investigated throughout the luteal phase and after luteal rescue with exogenous human chorionic gonadotrophin (hCG). The regulation of ER expression and oestradiol action was investigated in cultures of luteinised granulosa cells. ER subtypes ERb1 and ERb2 were localised throughout the luteal phase to steroidogenic cells in the human corpus luteum and cells of the surrounding stroma. Unlike follicular granulosa cells, steroidogenic cells in the corpus luteum showed minimal ERa immunostaining. The presence of endothelial cells in the granulosa cell layer with ERb1 and ERb2 positive nuclei was noted. ERb1 and ERb2 were differentially regulated across the luteal phase with ERb1 maximally expressed in the mid-luteal phase, while ERb2 expression was maximal in the early luteal phase. In vivo and in vitro, hCG had no long-term effect on ER expression, although in vitro hCG and oestradiol acutely down-regulated ERs. Treatment with oestradiol in vitro down-regulated 11b-hydroxysteroid dehydrogenase type 1 and inhibin bA subunit confirming a functional oestradiol response. These data highlight functional and differentially regulated oestradiol reception in human luteal cells.

“…The cyclic growth and differentiation of the corpus luteum are regulated by gonadotropins (Fraser et al 1999, Fraser & Lunn 2000, Wulff et al 2001a, Fraser & Duncan 2005. Within normal cycle, influenced by LH, the lifespan of the primate corpus luteum is generally restricted to 14 days.…”

Section: Functional Influence Of Hcg On Cell Junctional Proteins In Tmentioning

confidence: 99%

“…However, in case of pregnancy, due to hCG, it survives several months, which is called 'luteal rescue'. For the human corpus luteum, it has been demonstrated that luteal rescue is associated with the expansion of luteal vessels (Wulff et al 2001a), which probably includes the re-arrangement of cell-cell contacts such as junctional proteins. Therefore, it is of high interest to focus on hCG-dependent regulation of TJ and AJ in human corpus luteum.…”

Section: Functional Influence Of Hcg On Cell Junctional Proteins In Tmentioning

confidence: 99%

“…It has been shown, that inhibition of VE-Cadherin is followed by suppression of angiogenesis and degeneration of the vascular compartment in the mid-luteal phase corpus luteum (Nakhuda et al 2005). VEGF acts as a key molecule for the regulation of angiogenesis in the ovary (Wulff et al 2000(Wulff et al , 2001a(Wulff et al ,b,c, 2002. In addition, a close interrelation has been shown between VEGF and adhesion signaling pathways.…”

Section: Influence Of Vegf On Cell Junctional Proteins In the Primatementioning

confidence: 99%

See 1 more Smart Citation

Regulation of endothelial permeability in the primate corpora lutea: implications for ovarian hyperstimulation syndrome

Herr¹,

Bekes²,

Wulff³

2015

Self Cite

In a developing human corpus luteum, a closely regulated cellular communication system exists between the luteal steroidogenic cells and endothelial cells. This system guaranties the vascularization process during luteal formation. The process is combined with rapid release of large amounts of progesterone into the bloodstream. The regulation of endothelial proliferation and permeability by LH and human chorionic gonadotropin (hCG) is integral to this process. On the cellular level, endothelial permeability is regulated by intercellular junctions, such as adherens junctions (AJ) and tight junctions (TJ), which act as zipper-like structures between interacting endothelial cells. Several cell junctional proteins are localized to the corpus luteum, including Occludin, Nectin 2, Claudin 1, and Claudin 5, as well as, vascular endothelial (VE)-Cadherin. It has been assumed that regulation of AJ-and TJ-proteins is of particular importance for permeability, and accordingly, for the functionality of the corpus luteum in early pregnancy, because treatment with hCG induces downregulation of juntional proteins in the luteal vessels. The effect of hCG on the adhesive molecules is mediated by VE growth factor (VEGF). On a functional level, the hCG-dependent and VEGF-mediated decrease in junctional proteins causes a decrease in the density of cell-cell closure and, accordingly, an increase in endothelial permeability. In doing so, the different junctional proteins are not only directly influenced by VEGF but also interact among themselves and influence each other reciprocally. Disturbances in this strictly, regulated interactions may explain the development of pathologies with increased vascular permeability, such as the ovarian hyperstimulation syndrome.Reproduction (2015) 149 R71-R79