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Medical Research Council Reproductive Biology Unit, Center for Reproductive Biology (H.M.F., S.E.D., S.F.L., C.W., K.D.M.), Edinburgh, United Kingdom EH3 9ET; the Department of Cancer Medicine, Imperial College School of Medicine, Hammersmith Campus (V.A.C.), London, United Kingdom W12 0NN; and Molecular Angiogenesis Laboratories, Imperial Cancer Research Fund, Institute of Molecular Medicine, John Radcliffe Hospital (R.B.), Oxford, United Kingdom OX3 9DS
Address all correspondence and requests for reprints to: Dr. H. M. Fraser, Medical Research Council, Reproductive Biology Unit, Center for Reproductive Biology, 37 Chalmers Street, Edinburgh, United Kingdom EH3 9EW. E-mail: h.fraser{at}ed-rbu.mrc.ac.uk
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The aim of this study was to investigate the effects of immunoneutralization of vascular endothelial growth factor (VEGF) on the marmoset corpus luteum of the normal cycle as a means of exploring the role of angiogenesis in luteal function of the primate. VEGF has been shown to be expressed in the corpus luteum of the human and nonhuman primate and is therefore a likely candidate for targeting (10, 11, 12).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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VG76e was shown to be a blocking antibody by its inhibition of the growth stimulatory activity of VEGF on human umbilical vein endothelial cells (HUVEC), a gift from Prof. B. R. Binder, Vienna University (Vienna, Austria). The cells were cultured in medium 199 (Sigma, Poole, UK) with 20% heat-inactivated FBS (Sigma), 100 IU/ml penicillin/100 µg/ml streptomycin (Life Technologies, Inc., Paisley, UK), 250 ng/mL fungizone (Life Technologies, Inc.), 2 mM glutamine (Life Technologies, Inc.), 5 IU/ml heparin (Sigma), and 50 µg/ml endothelial cell growth supplement (ECGS) (Technoclone, Inc., Vienna, Austria). HUVEC (3 x 103) at passage 5 were plated in complete medium in 96-well plates and allowed to attach overnight. Growth was arrested by incubation with 100 µl reduced growth medium (medium 199 containing the supplements described above without ECGS and 2% FBS) for 24 h. Human VEGF (10 ng/ml; R&D Systems, Abingdon, UK) was added to wells with various concentrations of the anti-VEGF antibody (VG76e), a positive control anti-VEGF blocking antibody 2C3 (a gift from Prof. P. Thorpe, ME Medical Center, Portland, ME), or a negative control (mouse IgG, Sigma). Control wells received medium with or without VEGF. After 3 days of incubation, cell number was quantified colorometrically by the addition of 20 µl Cell Titer 96 Aqueous One Solution Cell Proliferation Assay (Promega Corp., Southampton, UK) at 492 and 620 nm reference filter. Background absorbance was determined with substrate alone and subtracted from all wells. Cell growth was calculated by subtracting absorbance in wells with cells grown without VEGF.
Animals
Common marmoset monkeys (Callithrix jacchus) were
housed in cages in rooms at a temperature of 22.5 C as described
previously (9). Adult females with a body weight of approximately
350 g, with regular ovulatory cycles, were housed together with a
younger sister or prepubertal female. Blood samples were collected
three times per week by femoral venipuncture without anesthesia, and
plasma was stored at -20 C until required for progesterone assay to
confirm normal ovulatory cycles. Criteria for the occurrence of
ovulation and normal luteal phase length (18–22 days) were based on
determination of plasma progesterone concentrations as described
previously (13).
Treatment
The experiments were carried out in accordance with the Animals
(Scientific Procedures) Act, 1986. To synchronize timing of ovulation
during the treatment cycle, animals were treated with 1 µg
PGF2
analog (Planate, Coopers Animal Health
Ltd., Crewe, UK), im, during the mid- to late luteal phase of the
pretreatment cycle to induce luteolysis. This treatment is normally
followed by ovulation 10 days later (14). Four marmosets were treated
with VEGF antibody at a concentration of 2.7 mg/ml starting 10 days
after PG, i.e. the day of anticipated ovulation (luteal
phase day 0), at a dose of 2 mg followed by 1 mg on days 1 and 2 (early
luteal group). Four controls were treated with the same dose of mouse
-globulin (Sigma) following the same schedule.
Treatment was extended to the midluteal phase in an additional six
marmosets; additional injections of 1 mg anti-VEGF were administered on
days 3, 5, 7, and 9, with six animals receiving mouse -globulin as
controls (midluteal group). All treatments were given by slow iv
injection.
Ovaries were obtained the day after final treatment, luteal day 3 or 10, after the animals had received 20 mg bromodeoxyuridine (BrdU: Roche Molecular Biochemicals, Essex, UK) in saline by slow iv injection. One hour later, the animals were sedated using 100 µl ketamine hydrochloride (Parke-Davis Veterinary, Pontypool, UK), im, and killed with an iv injection of 400 µl Euthetal (sodium pentobarbitone, Rhone Merieux, Harlow, Essex, UK). Ovaries were removed immediately, weighed, fixed in 4% paraformaldehyde for 24 h, dehydrated, and embedded in paraffin. In addition, a small portion of a representative corpus luteum was placed in 3% glutaraldehyde in 0.1 M cacodylate buffer, pH 7.3. These specimens were fixed for 2 h, rinsed in the same buffer, postfixed in buffered 2% osmium tetroxide for 2 h, and embedded in Araldite after dehydration in ethyl alcohol. Semithin (1 µm) sections were stained with toluidine blue for light microscope analysis. When the midluteal group was examined, it was apparent that the density of the lutein cells was increased after treatment. To quantify this change, paraffin sections were stained with hematoxylin and eosin, and lutein cell density was determined in 12 corpora lutea/group.
The establishment and function of the corpus luteum were determined by measuring plasma progesterone concentrations in daily blood plasma samples as described previously (13). Only marmosets in which treatment was started at the time of presumptive ovulation (13) (plasma progesterone having reached >30 nmol/liter and found retrospectively to be sustained at luteal phase values) were included in the study. Analysis of differences in plasma progesterone concentrations was performed by repeated measures ANOVA followed by post-hoc Fisher’s protected least significant difference test (when a significant interaction was found).
Immunocytochemistry
Cellular responses were studied by determining the number of
mitotic cells, after BrdU administration as a marker, and by examining
the establishment of the microvascular network using factor VIII
staining to identify endothelial cells. Tissue sections (5 µm) were
cut onto Tespa-coated (Sigma) slides for
immunocytochemistry and morphological examination. Sections were
stained with hematoxylin and eosin and examined for morphological
features of apoptosis as described previously (15). Localization of
factor VIII was determined by immunocytochemistry as described
previously (16); visualization was performed with nitro blue
tetrazolium. These sections were not counterstained, so that
quantitative image analysis could be performed; the corpora lutea were
identified from the hematoxylin- and eosin-stained sections.
Immunostaining for factor VIII to compare control and treated animals
was carried out in separate runs for the early and midluteal groups.
Factor VIII immunostaining was quantified using the Image Pro-Plus 3.0
(Media Cybernetics, Silver Spring, MD) image analysis program. Four to
six randomly chosen areas of 13.3 x 104
µm2 for the early luteal sections, and 5.3
x 104 µm2 for the larger
midluteal sections were studied; in total, these areas covered
approximately two thirds of each corpus luteum. The captured gray scale
image was thresholded and converted to a binary image, and the factor
VIII-positive area was quantified. The mean of these areas per corpus
luteum was taken as representative for that animal.
Proliferating cells were visualized in ovarian sections using a mouse monoclonal antibody to BrdU (Roche Molecular Biochemicals) as described previously (9). Cell proliferation was assessed by counting the number of BrdU-positive cells in six randomly chosen fields of 62,500 µm2/corpus luteum and expressed as a mean percentage of the total cells in these fields. For factor VIII quantification, proliferation index, ovarian weight, and luteal cell numbers, differences between groups were determined using a two-tailed unpaired t test; P < 0.05 was taken as the level of significance.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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).
These results indicate that VG76e is a blocking antibody that inhibits
the growth stimulatory activity of VEGF.
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). It was clear that few (if any) of
the hormone-producing cells had incorporated BrdU; positive staining
was restricted to some cells surrounding the luminal microvessels and
others whose appearance was consistent with that of capillary
endothelial cells. We have shown previously that cells incorporating
BrdU have the location and morphological appearance of endothelial
cells (9). In addition, colocalization studies have demonstrated that
more than 80% proliferating cells stain with endothelial cell markers
(17). Proliferation was high within the corpora lutea from control
marmosets and was markedly reduced by anti-VEGF treatment (Fig. 2b), as
confirmed by the decreased proliferation index (Fig. 2c). Factor VIII
immunostaining demonstrated the initiation of the development of the
microvasculature in control corpora lutea (Fig. 2d), but although there
was an indication of reduced capillary number associated with anti-VEGF
treatment (Fig. 2e), quantification of factor VIII immunostaining
showed no significant difference at this time (Fig. 2f).
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). Some proliferation was also evident
in all the corpora lutea from the anti-VEGF-treated marmosets (Fig. 3b), and the proliferation index showed no significant treatment
differences (Fig. 3c). However, whereas in control corpora lutea
staining for factor VIII revealed that a fully developed
microvasculature had been established (Fig. 3d), treatment with
anti-VEGF resulted in corpora lutea with a much lower degree of
vascularization and the absence of an extensive capillary bed, similar
to that observed in the early luteal phase (Fig. 3e). Quantification of
factor VIII immunostaining showed a marked suppression of endothelial
cell area associated with treatment (Fig. 3f).
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). Within
the cytoplasm were mitochondria and lysosomes together with occasional,
less basophilic inclusions typical of lipid droplets. In some tissue
sections a few lutein cells showed varying degrees of basophilia,
although it was not possible to determine whether cytoplasmic density
was correlated with distinct differences in organelle or inclusion
content. The lutein cells were supported by connective tissue,
including fibroblasts, and there was an extensive blood supply
characterized by the occurrence of endothelial cell nuclei and numerous
lumina, often containing erythrocytes. In the corpora lutea from the
midluteal anti-VEGF-treated marmosets, lutein cells appeared more
densely packed (Fig. 4b), with a closer contact with neighboring lutein
cells. Quantification of lutein cell number showed that numbers of
lutein cells per area were significantly greater (P <
0.001) in the treated group (103.8± 5.5, for controls vs.
79.2 ± 3 after anti-VEGF). In addition, numerous clusters of
basophilic cells, presumably lutein, were present principally in the
central area of the corpus luteum. Higher magnification revealed that
although the majority of the lutein cells had retained their integrity,
they exhibited an increased occurrence of lipid droplets in the
peripheral zone of the cytoplasm identified by their gray coloration
and homogeneous appearance (Fig. 4d).
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Discussion |
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The absence of marked morphological change in the lutein cells after treatment contrasts with observations on the characteristic effects of withdrawal of the tropic factor, LH, which we have described recently (17, 19). Such treatment also results in inhibition of early luteal angiogenesis, but this is secondary to the destruction of the lutein cells, in which it is assumed most of the principal angiogenic factors are produced (10, 11, 12, 17). The observed changes in the structure of the corpus luteum after neutralization of VEGF are likely to result from the specific inhibition of angiogenesis. The increased density of the lutein cells results primarily from the dearth of capillaries, whereas the occurrence of aggregates of subsets of lutein cells with more densely stained nuclei and cytoplasm, found principally in the central area of the corpus luteum, suggests a premature onset of cell death, an observation that would be compatible with a failure of blood vessel development to deliver essential survival factors. The increased presence of lipid droplets is more difficult to explain, but suggests either a lack of tropic hormone stimulus for steroid hormone release or a failure of the normal secretory process. The accumulation of lipid is often associated with the onset of degenerative change in steroid-producing cells, including the early stages of luteolysis in the marmoset (19). Despite the absence of major structural effects within lutein cells, secretion of the principal steroidal hormonal product of these cells is reduced by 60%. The most likely explanation for these findings is that the reduction in development of the microvasculature deprives the lutein cells of both the low density lipoprotein precursors necessary for progesterone production and the transport system for efficient release of their products into the bloodstream. Some effects of the treatment could also be related to an inhibition of the vascular permeability properties of VEGF, although this was not studied specifically. It is also conceivable that the treatment could have an inhibitory effect on pituitary LH secretion. However, we have recently shown that suppression of LH during the luteal phase results in characteristic and marked changes in the morphology of the lutein cells (19) that were not observed in this study, indicating that any change in LH secretion would be minor, making detection of any change unlikely using existing assays and with the sampling frequency employed.
The present results are in agreement with a recent report in the immature rat in which VEGF was inhibited while follicle development and multiple ovulations were induced by PMSG and hCG, respectively (6). However, in the rat model, as VEGF antagonist treatment was initiated before the onset of follicular hyperstimulation, it was not possible to dissociate the luteal inhibition from the consequences of inhibition of angiogenesis in the developing follicle.
Because angiogenesis inhibitors are currently being developed primarily for treatment of vascular solid tumors and are also likely to have a role in the control of rheumatoid arthritis, retinal neovascularization, and psoriasis it is essential that their potential effects on the reproductive system and its function be determined. In addition, the potential of using such inhibitors as antifertility agents is currently generating considerable interest. However, it is unlikely that all angiogenesis inhibitors identified in studies using nonprimate species will influence fertility, as shown by our findings in the marmoset, in which TNP-470 was administered in a protocol similar to that used in the present study but had no inhibitory effect on luteal angiogenesis (9).
As we have shown that luteal inadequacy is associated with inhibition of angiogenesis, this suggests that the clinical incidence of these conditions may in part be the result of defects in the angiogenic process. They may therefore prove to be amenable to treatment with angiogenic growth factors such as VEGF. The potential to inhibit angiogenesis in the female reproductive tract should have important implications for clinical practice, but the development of safe and effective strategies will require detailed investigation of suitable animal models, as described in this study. Finally, manipulation of VEGF in this fashion should provide a novel approach to investigate the precise physiological role of VEGF in ovarian angiogenesis.
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Acknowledgments |
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Footnotes |
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Received October 8, 1999.
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S.F. Lunn, H.M. Fraser, and H.D. Mason Structure of the corpus luteum in the ovulatory polycystic ovary Hum. Reprod., January 1, 2002; 17(1): 111 - 117. [Abstract] [Full Text] [PDF]
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C. Wulff, H. Wilson, J. S. Rudge, S. J. Wiegand, S. F. Lunn, and H. M. Fraser Luteal Angiogenesis: Prevention and Intervention by Treatment with Vascular Endothelial Growth Factor TrapA40 J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3377 - 3386. [Abstract] [Full Text] [PDF]
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C. Wulff, S. J. Wiegand, P. T. K. Saunders, G. A. Scobie, and H. M. Fraser Angiogenesis During Follicular Development in the Primate and its Inhibition by Treatment with Truncated Flt-1-Fc (Vascular Endothelial Growth Factor TrapA40) Endocrinology, July 1, 2001; 142(7): 3244 - 3254. [Abstract] [Full Text] [PDF]
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 N. Ferrara Role of vascular endothelial growth factor in regulation of physiological angiogenesis Am J Physiol Cell Physiol, June 1, 2001; 280(6): C1358 - C1366. [Abstract] [Full Text] [PDF]
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L. P. Reynolds and D. A. Redmer Angiogenesis in the Placenta Biol Reprod, April 1, 2001; 64(4): 1033 - 1040. [Abstract] [Full Text]
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R. C. Zimmermann, E. Xiao, N. Husami, M. V. Sauer, R. Lobo, J. Kitajewski, and M. Ferin Short-Term Administration of Antivascular Endothelial Growth Factor Antibody in the Late Follicular Phase Delays Follicular Development in the Rhesus Monkey J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 768 - 772. [Abstract] [Full Text]
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C. Wulff, H. Wilson, P. Largue, W. C. Duncan, D. G. Armstrong, and H. M. Fraser Angiogenesis in the Human Corpus Luteum: Localization and Changes in Angiopoietins, Tie-2, and Vascular Endothelial Growth Factor Messenger Ribonucleic Acid J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4302 - 4309. [Abstract] [Full Text]
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 S. Hague, L. Zhang, M. K. Oehler, S. Manek, I. Z. MacKenzie, R. Bicknell, and M. C. P. Rees Expression of the Hypoxically Regulated Angiogenic Factor Adrenomedullin Correlates with Uterine Leiomyoma Vascular Density Clin. Cancer Res., July 1, 2000; 6(7): 2808 - 2814. [Abstract] [Full Text]
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S. E. Dickson and H. M. Fraser Inhibition of Early Luteal Angiogenesis by Gonadotropin-Releasing Hormone Antagonist Treatment in the Primate J. Clin. Endocrinol. Metab., June 1, 2000; 85(6): 2339 - 2344. [Abstract] [Full Text]
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) and anti-VEGF-treated marmosets (•). Treatment started on the
day of expected ovulation and is associated with a significant
suppression (P < 0.001). Values are the mean
± SEM (n = 6/group).