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1 Deparment of Anatomy, University of Essen, Hufelandstr. 55, D-45122, Essen, Germany
2 Department of Cell Biology, University of Essen, Essen, Germany
3 University Clinic for Gynecologic, Endocrinology and Reproductive Medicine, RWTH Aachen, Germany
(Requests for offprints should be addressed to R Gruemmer; Email: ruth.gruemmer{at}uni-essen.de)
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Abstract |
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Introduction |
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The role of the avascular granuslosa layer in controlling angiogenesis in the developing follicles still appears to be controversial. Experimental evidence suggests that granulosa cells are also the source of angiogenesis inhibitors, such as hyaluronic acid (Tempel et al. 2000) and 2-methoxyestradiol (Shang et al. 2001). However, detailed studies investigating the cascade of events controlling angiogenesis during folliculogenesis and corpus luteum formation in the human have not been reported. This is of special interest as defects in ovarian angiogenesis contribute to a variety of disorders including anovulation and infertility, pregnancy loss, ovarian hyperstimulation syndrome, and ovarian neoplasms (Neulen et al. 1995, Abulafia & Sherer 2000, Geva & Jaffe 2000a).
In order to investigate the role of follicular fluid constituents and of granulosa cells in the expression of angiogenesis-related endothelial genes, human endothelial cells were incubated in vitro with human follicular fluid or culture medium conditioned by human granulosa cells. Gene expression was evaluated by microarray technology, and transcriptomes of the differently treated endothelial cells were compared with regard to the regulation of angiogenic and antiangiogenic genes.
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Follicular fluid was obtained by follicular aspiration from 12 follicle-stimulating hormone (FSH)-treated women (mean age 34.5 years) undergoing oocyte retrieval for in vitro fertilization (IVF/ICSI) at the Department of Gynecological Endocrinology at the University Hospital, Aachen, Germany. IVF/ICSI was performed due to andrological reasons (5), tubal occlusion (4), endometriosis (1) or idiopathic reasons (2). Ovarian stimulation was induced with recombinant human FSH (Gonal F, Serono, Unterschleissheim, Germany; mean dosage per cycle: 2300 U) after pituitary desensitization with Nafarelin (Pharmacia, Freiburg, Germany; 400 µg daily intranasally). Oocyte retrieval was carried out 36–37 h after human chorionic gonadotropin (hCG) (Pregnesin, Serono) administration at a total dose of 5000 IU. After removal of oocytes, follicular fluid from each single patient was pooled (3 to 30 follicles/patient), centrifuged at 800 g for 5 min and the supernatant was frozen at –20 °C until use.
The experimental design was approved by the local ethical committee of the University Clinic Aachen (# EK 2008). Written informed consent was obtained from patients individually.
Granulosa cell culture
Human granulosa cells were obtained by follicular aspiration from FSH-treated women undergoing oocyte retrieval for IVF/ICSI as described above. After centrifugation and removal of follicular fluid, the cell pellet was dissolved in 1 ml PBS solution containing 20 IU hyaluronidase and incubated for 12 min at 37 °C. Cells were washed with PBS, centrifuged, suspended in 1 ml PBS and separated from red blood cells by centrifuging through a Percoll gradient (50%; Biochrom, Berlin, Germany) at 2000 g for 10 min. Granulosa cells were carefully removed, suspended in 1 ml culture medium, centrifuged at 500 g for 5 min, resuspended in 1 ml culture medium and the cell number was evaluated. Cells were plated at a density of 5 x 105 cells/well in 6-well dishes (Costar, Bodenheim, Germany) and cultured in M199 Earle’s Medium (Biochrom) supplemented with 10% FCS, 2 mM L-glutamine, and 1% penicillin/strepomycin at 37 °C in 95% air-5% CO2 humidified environment. Cell culture medium was changed after 24 h and was then harvested after 4 days of culturing and stored at –20 °C until use in further experiments.
Endothelial cell culture
For isolation of human umbilical vein endothelial cells (HUVECs), umbilical cords were obtained immediately after term deliveries and umbilical veins were flushed with PBS, filled with 10 ml phosphate buffered salt solution (PBS) containing 0.1% collagenase/dispase, and incubated for 30 min at 37 °C. Veins were then flushed with 40 ml culture medium which was collected in a 50-ml tube, the cell-containing medium was centrifuged at 1200 r.p.m. for 8 min, the pellet was resuspended in culture medium (Endothelial Cell Growth Medium-2; Clonetics, Cambrex, Vervier, Belgium) and the cells were routinely cultured as monolayers through serial passaging in 25-cm2 plastic cell culture flasks (Falcon, Heidelberg, Germany). Culture medium was changed at two-day intervals. When the cultures became confluent they were passaged by exposure to 0.05% trypsin/0.02% EDTA (Gibco BRL, Germany).
For each experiment, HUVECs of 3–5 umbilical veins were pooled and cells were seeded at a density of 0.5 x 106 cells/well in 6-well plates. After two days of culturing, cells were confluent and were incubated with 6-ml culture medium or with 4.5-ml culture medium supplemented with 1.5 ml follicular fluid or 1.5 ml granulosa cell conditioned medium respectively. After 4 days of incubation at 37 °C endothelial cells were harvested and frozen at –20 °C until RNA preparation.
For single comparisons of HUVECs treated with follicular fluid, endothelial cells were separately incubated with the follicular fluid of 9 different patients and compared with 2 different controls. For array analysis of HUVECs treated with granulosa cell conditioned medium, RNA of HUVECs treated separately with the granulosa cell conditioned medium of 3 different patients was pooled and compared with pooled RNA of 3 different controls.
Microarray analysis
Microarray analysis was performed for each of the 9 HUVECs probes incubated with follicular fluid from different patients and for the two controls. To evaluate the effect of granulosa cell conditioned medium, one array was carried out of the pooled RNA of 3 treated HUVECs probes and one array of the pooled RNA of 3 controls.
Total RNA was isolated from HUVECs using a Qiagen RNeasy kit (Qiagen, Hilden, Germany) according to the manufacturer’s protocol. Total RNA (8–10 µg) was converted into double-stranded cDNA using a modified oligo-dT primer including a 5' T7 RNA polymerase promoter sequence (Dürig et al. 2003). The resulting cDNA was transcribed in vitro with T7 RNA polymerase in the presence of a mixture of ATP, CTP, UTP, GTP, biotin-11-CTP, and biotin-16-UTP as described previously (Dürig et al. 2003). Purified cRNAs were heat-fragmented in 40 mM Tris–acetate pH 8.1, 100 mM K+ acetate, and 30 mM Mg2+ acetate at 94 °C for 30 min. Human Genome HG-U133A microarrays (Affymetrix, High Wycombe, Herts, UK) with more than 22 000 probe sets were hybridized, washed, and stained according to the manufacturer’s recommendations, involving a three-step staining and amplification procedure with streptavidin-phycoerythrin (SAPE), a biotinylated anti-streptavidin antibody, and a final SAPE step. The fluorescence intensities for the individual oligonucleotide probes on the arrays were determined with a confocal scanner from Affymetrix.
Affymetrix Microarray Suite 5.0 (MAS 5.0) software was used to determine the signals and detection calls of the individual probe sets. Scaling across all probe sets (global scaling) of a given array to a target intensity of 1000 was included to compensate for variations in the amount and quality of the cRNA samples and other experimental variables. In a next step, pair wise comparison analyses of experimental and baseline arrays were performed by MAS 5.0 comparison analysis to determine expression changes as well as significance of change and number of comparisons which show a change, which are based on a statistical evaluation of the signals at the individual probe pair level. Filtering of the comparison results was performed using the Affymetrix Data Mining Tool 3.0. Individual cut-offs applied to the data sets are given in the legend to Table 2
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RT-PCR was carried out with RNA of HUVECs treated with the follicular fluid of 10 different patients which had not been included in the microarray studies, and of 5 controls.
Total RNA (2 µg) of HUVECs was digested with DNase I (Invitrogen, Karlsruhe, Germany) for 15 min at room temperature and processed to cDNA by reverse transcription (RT) with M-MLV reverse transcriptase (Invitrogen, Karlsruhe, Germany) in a total volume of 50 µl. RT was performed at 37 °C for 60 min in a thermocycler (Biometra, Goettingen, Germany). Four microliters of the RT-reaction were used for PCR experiments. The target and the endogenous control (ß-actin) amplifications were run in one tube (for primers see Table 1). PCR reaction was performed in a 50 µl volume using BioTherm Taq polymerase (Genecraft, Muenster, Germany) for 36 amplification cycles of 1 min denaturation at 94 °C, 1 min annealing at 59 °C and 1.5 min elongation at 72 °C. The PCR amplification was followed by a 10-min final extension at 72 °C. The generated PCR amplification products were electrophoresed on a 2% agarose gel and detected by ethidium bromide staining. With densitometric analysis using Gel imager (Intas, Goettingen, Germany) PCR products were normalized to ß-actin and relatively quantified (Gelscan Professional V4.0, BioSciTec, Frankfurt, Germany).
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Results |
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Using gene-chip expression arrays we have analyzed more than 22 000 probe sets in untreated monolayers of HUVECs (n=2) and compared them with the gene expression in HUVECs treated with follicular fluid (n=9), resulting in 18 comparisons. Those genes were evaluated which were significantly up- or down-regulated at least 2.5-fold and which were regulated in more than 70% of comparisons. Using these stringent selection criteria, we identified a total of 15 genes that were up-regulated (3.2– to 24.3-fold) and 11 genes that were down-regulated (3.3– to 14.9-fold) in HUVECs treated with follicular fluid (Table 2
). The regulated genes include many genes involved in angiogenesis. Up-regulated genes known to be involved in angiogenesis were gro-beta (16.5-fold increase on average), Ang-2 (3.9-fold increase), E-selectin (5.3-fold increase), alpha-2-macroglobulin (24.3-fold increase), and vascular cell adhesion molecule-1 (VCAM-1) (4.4-fold increase), whereas a significant down-regulation of fibulin-5 (3.5-fold decrease) and elastin (14.9-fold decrease) could be observed.
Up- and down-regulated genes in HUVECs treated with granulosa cell conditioned medium
To analyze if the observed gene regulation induced by follicular fluid is mediated by factors produced by granulosa cells, HUVECs were treated with granulosa cell conditioned medium or with the corresponding follicular fluid of the same patients. Gene expression of those treated endothelial cells was compared with untreated controls by gene array analysis as described. In this experimental approach, HUVECs treated with granulosa cell conditioned medium (n=4) or with follicular fluid (n=4) as well as untreated controls (n=4) were pooled and for each experimental approach one array was performed. Genes which showed a significant up- or down-regulation are shown in Table 3. Most of the genes found to be regulated by follicular fluid were similarly regulated by incubation with medium supernatant of granulosa cells including up-regulation of gro-beta, E-selectin and down-regulation of fibulin-5 and elastin. VCAM-1, however, which was up-regulated in endothelial cells by incubation with follicular fluid in 15 out of 18 comparisons (see Table 2), was down-regulated by incubation with granulosa cell conditioned medium (Table 3). Also in this experiment, Ang-2 was up-regulated in endothelial cells by incubation with follicular fluid, but no regulation was observed after treatment with granulosa cell conditioned medium.
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To confirm the finding of the array analysis, RT-PCR was performed in HUVECs treated with follicular fluid for those genes possibly involved in angiogenesis. A significant increase of gene expression was observed for gro-beta (43-fold), Ang-2 (1.43-fold), and E-selectin (2.15-fold) compared with untreated controls (Fig. 1). The increase in VCAM-1 expression which had been observed in microarray analysis (Table 1) could be confirmed by RT-PCR (1.23-fold increase), but was not significant here. Elastin gene expression as well as mRNA expression of fibulin-5 were significantly decreased (6.8-fold and 1.48-fold respectively) in HUVECs incubated with follicular fluid compared with untreated controls (Fig. 1).
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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The most prominent up-regulated anti-angiogenic gene detected was the chemokine gro-beta (MIP-2a). Gro-beta enhances monocyte adhesion to endothelial cells (Hagiwara et al. 1998), inhibits growth factor-stimulated proliferation of capillary endothelial cells, and the growth of Lewis lung tumors was curtailed by suppression of tumor-induced neovascularization (Cao et al. 1995).
A significant up-regulation could also be demonstrated for Ang-2 and for alpha-2-macroglobulin in HUVECs treated with follicular fluid; however, no significant regulation after treatment with granulosa cell conditioned medium could be observed. This could be due to too low a concentration of regulating factors secreted by granulosa cells into the culture medium. Moreover, factors contained in follicular fluid regulating these genes might originate from blood serum rather than from granulosa cells.
Ang-1 and Ang-2 are vascular endothelial cell-specific growth factors that play important roles during angiogenesis by binding to their tyrosine kinase receptor, Tie2 (Davis et al. 1996, Maisonpierre et al. 1997, Geva & Jaffe 2000b). Ang-2 was found to disrupt blood vessel formation by antagonizing the effect of Ang-1 and Tie2, and was thus considered to represent a natural Ang-1/Tie2 inhibitor (Maisonpierre et al. 1997, Asahara et al. 1998). The balance between the Ang-2:Ang-1 ratio and VEGF expression is important for the regulation of angiogenesis (Goede et al. 1998, Wulff et al. 2000) and the Ang/Tie system is supposed to be involved in the angiogenetic changes that occur during follicular development (Maisonpierre et al. 1997, Goede et al. 1998, Hazzard et al. 1999, Wulff et al. 2000, Hayashi et al. 2003) as well as in pathological angiogenesis in the ovary (Hata et al. 2002). The proteinase inhibitor alpha-2-macroglobulin has been shown to bind to VEGF (Bhattacharjee et al. 2000) and thus may have an influence on VEGF action. The up-regulation of alpha-2 macroglobulin gene expression also supports anti-angiogenic properties of follicular fluid.
In contrast to these results, transcription of the pro-angiogenic factors elastin and fibulin-5 was significantly down-regulated in endothelial cells treated with follicular fluid or granulosa cell conditioned medium. Fibulin-5 (also known as EVEC/DANCE) is an integrin-binding extracellular matrix protein abundantly expressed in vascular endothelial cells of vessels which contain elastic fibers and in developing arteries(Kowal et al. 1999, Nakamura et al. 1999). In addition, it provides anchorage of elastic fibers to cells by binding to elastin, thereby stabilizing and organizing elastic fibers in the vasculature (Midwood & Schwarzbauer 2002, Nakamura et al. 2002, Yanagisawa et al. 2002, Kuang et al. 2003).
The expression of fibulin-5 is up-regulated during vascular growth and maturation in lesions of injured vessels (Kowal et al. 1999). It could be shown that the absence of fibulin-5 did not alter the proliferative effect of elastin, but rather perturbed elastic fiber architecture (Nakamura et al. 2002). In addition to its structural function, elastin provides an anti-proliferative effect on vascular smooth muscle cells, and elastin null mice died perinatally due to vascular occlusion (Li et al. 1998).
E-selectin is a calcium-dependent lectin that mediates adhesive interactions of circulating leucocytes with the vascular endothelium. It is synthesized and expressed on activated endothelial cells and can be induced by inflammatory cytokines (Bevilacqua et al. 1987, Carlos & Harlan 1994). Elevated levels of soluble E-selectin have been found in patients with vasculoproliferative disorders such as rheumatoid arthritis (Koch et al. 1993) and tumor growth (Benekli et al. 1998, Hebbar & Peyrat 2000). E-selectin is a potent angiogenic mediator as it could be shown to induce an increase in HUVEC tube formation in the Matrigel in vitro assay (Kumar et al. 2003). VCAM-1 has been correlated to angiogenesis and could be detected in human follicular fluid (Benifla et al. 2001). In the microarray analysis, the expression of VCAM-1 was enhanced in HUVECs incubated with follicular fluid; however, this regulation was not confirmed as significant using RT-PCR.
Recently, experimental evidence suggested that granulosa cells produce and follicular fluid contains pro-angiogenic cytokines such as VEGF (Ravindranath et al. 1992, Yan et al. 1993, Kamat et al. 1995, Neulen et al. 1995, 1998, Doldi et al. 1997, Laitinen et al. 1997, Otani et al. 1999, Berisha et al. 2000). In addition to pro-angiogenic molecules, negative regulators of angiogenesis were observed (Tempel et al. 2000, Shang et al. 2001, Grasselli et al. 2003). The present work demonstrates that factors contained in follicular fluid regulate the transcription of angiogenesis-modulating genes in endothelial cells and thus could help to explain the temporal and spatial discrepancy between the high expression of VEGF and the restricted angiogenesis in the preovulatory follicle. Follicular fluid may provide a molecular shield that prevents premature vascularization of the preovulatory follicle. The balance of these regulatory factors is presumed to change according to the stage of follicular development. Though follicular fluid and granulosa cells were isolated from IVF patients and thus had been exposed to hCG, they were still pre-ovulatory and can be helpful to evaluate molecular mechanisms involved in the regulation of ovarian angiogenesis.
HUVECs exposed to follicular fluid or luteinized human granulosa cell conditioned media exhibit both the expression of pro- and anti-angiogenic genes. Angiogenesis is strictly controlled by a balance of pro-and anti-angiogenic regulators (Hanahan & Folkman 1996) resulting in temporal and spatial tightly regulated angiogenesis and vessel function. Our data suggest the production of angiogenesis-modulating factors by granulosa cells of peri-ovulatory follicles in humans with regard to gene transcription. However, the regulation of protein level as well as the impact on the biological function of endothelial cells still has to be evaluated. Understanding the molecular mechanisms which regulate the complex process of angiogenesis is a major challenge, with implications for the understanding of angiogenesis in reproductive biology as well as in pathological conditions.
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Acknowledgements |
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Received 30 August 2004
Accepted 6 October 2004
Made available online as an Accepted Preprint 20 October 2004
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D. H. M. Lozano, N. Frydman, J. M. Levaillant, S. Fay, R. Frydman, and R. Fanchin The 3D vascular status of the follicle after HCG administration is qualitatively rather than quantitatively associated with its reproductive competence Hum. Reprod., April 1, 2007; 22(4): 1095 - 1099. [Abstract] [Full Text] [PDF]
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