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BOR - Papers in Press, published online ahead of print December 11, 2002.
Biol Reprod 2002, 10.1095/biolreprod.101.000679
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BIOLOGY OF REPRODUCTION 68, 1736–1741 (2003)
DOI: 10.1095/biolreprod.101.000679
© 2003 by the Society for the Study of Reproduction, Inc.

Ovary

Vascular Endothelial Growth Factor Stimulates Preantral Follicle Growth in the Rat Ovary1

Douglas R. Danforth2, Laura K. Arbogast, Sue Ghosh, Alexandra Dickerman, Rana Rofagha, and Chad I. Friedman

Department of Obstetrics and Gynecology, The Ohio State University, Columbus, Ohio 43210


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The regulation of preantral follicle growth in mammals is poorly understood. The availability of an adequate vascular supply to provide endocrine and paracrine signals may be important during the early states of follicle growth as well as the later states of follicle selection and dominance. The objective of the present study was to investigate whether vascular endothelial growth factor (VEGF) plays a role in preantral follicular development in the rat ovary. Immature (age, 21 days) Sprague-Dawley rats were injected with 500 ng of VEGF in saline or 50 µg of diethylstilbestrol (DES) in oil under the bursa of one ovary. The contralateral ovary was injected with a corresponding volume of vehicle. Rats were killed 48 h later, and the ovaries were removed and analyzed histologically. Intrabursal administration of VEGF significantly increased the number of primary and small secondary, but not of large secondary, preantral follicles in the ovary, similar to the effect of DES (P < 0.05). The VEGF stimulated preantral follicle growth in a time- and dose-dependent manner. Subcutaneous DES administration increased the number of primary and secondary follicles, and both s.c. and intrabursal estrogen administration stimulated VEGF protein expression in the rat ovary. These data indicate that VEGF stimulates preantral follicular development in the rat ovary, is regulated by estrogen, and may be one of the factors that participate in the regulation of early follicle growth in the rat.

follicle, follicular development, granulosa cells, growth factors, ovary


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The regulation of folliculogenesis in the mammalian ovary is a complex process. Whereas the later stages of gonadotropin-dependent follicle growth have been more thoroughly studied, the early stages of folliculogenesis, especially the initiation of follicle growth, remain enigmatic. Accumulating evidence during the past decade suggests that the initiation of folliculogenesis is a continuous process regulated by a variety of endocrine and paracrine signals [1]. Moreover, species differences in this process are likely to exist as well [2, 3].

Estrogen has repeatedly been shown to enhance early follicle growth and follicular development in the rat [4–6], though such an effect has not been documented in primates [2, 3]. That estrogen enhances the number of follicles progressing to the early antral stage, but is not essential, has been adequately demonstrated by the aromatase knockout mouse [7], the estrogen ß receptor knockout mouse [8], and the estrogen {alpha} receptor knockout mouse [9]. In these models, as well as in aromatase-deficient women [10], numerous antral follicles are observed within the ovary.

It has been suggested that the availability of an adequate vascular supply to provide endocrine and paracrine signals may play a key role in the regulation of follicle growth [11]. Vascular endothelial growth factor (VEGF) is one of the key factors regulating angiogenesis in the ovary. Several investigators [12–14] have demonstrated a primary role of VEGF in corpus luteum angiogenesis by neutralizing VEGF activity: Despite the production of other angiogenic factors, neutralization of VEGF activity prevented normal development and function of the corpus luteum.

Vascular endothelial growth factor may also be important in the regulation of follicle growth. Numerous studies indicate that VEGF is produced by thecal and/or granulosa cells in the ovary [15–21]. Gonadotropins have repeatedly been shown to stimulate VEGF production by granulosa cells [12, 22–24]. In rats and primates, VEGF expression by granulosa cells is readily apparent following the LH ovulatory surge. Concentrations of VEGF in follicular fluid have been shown to increase around the time of the LH surge in humans [25]. In addition, follicular fluid VEGF concentrations correlate with follicular fluid progesterone concentrations following FSH and hCG administration [26]. Continued expression of VEGF mRNA by the luteinized granulosa cells is readily detected during the early and midluteal phase [27]. Neutralization of VEGF activity with neutralizing antibodies [28] or a soluble form of the VEGF receptor [29] disrupts follicle growth and granulosa cell proliferation in monkeys.

Follicle activation is associated with increased VEGF production and increased blood vessel extension [30].The extremely high intraovarian levels of VEGF increase the possibility that paracrine interactions with other ovarian compartments might exist. We hypothesize that, in addition to its well-established effects on the latter stages of folliculogenesis, VEGF may be important during the early stages of preantral follicle growth. The present study was designed to investigate the effects of exogenous VEGF on early follicle growth and to examine the potential regulation of VEGF expression by estrogen in the rat ovary.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals

All studies were approved by the Institutional Laboratory Animal Care and Use Committee at The Ohio State University and were in accordance with the National Institutes of Health guide for the care and use of laboratory animals. Immature female Sprague-Dawley rats were anesthetized with ketamine HCl (80 mg/kg; Fort Dodge Laboratories, Fort Dodge, IA) and xylazine (4 mg/kg; The Butler Company, Columbus, OH), and the dorsal lumbar region was prepared for surgery. A 1.5-cm midline incision was made, and the opening was moved to the flank for entrance into the abdominal cavity through the muscle and peritoneum. The uterine horn was grasped with forceps and the ovary exteriorized. Rats then received a 2-µl injection of either recombinant VEGF (5–1000 ng; R&D Systems, Inc., Minneapolis, MN) in saline or diethylstilbestrol (DES; 50 µg; Sigma Chemical Co., St. Louis, MO) in oil under the bursa of one ovary. Because rat VEGF was not commercially available at the time, the initial experiment (see Fig. 1) was performed with human VEGF. All subsequent studies were performed with rat VEGF. Injections were performed under an operating microscope using pulled-glass micropipettes (Narishige PB-7 micropipette puller; Narishige, Tokyo, Japan) attached to a Narishige IM-5b injector and an MO-108 micromanipulator (Narishige). Injection solutions were prepared with trypan blue dye to visualize accuracy of injection. Any injection resulting in leakage of dye was considered to be a failure, and that animal was not included in the present study. The contralateral ovary was then exteriorized in the same manner and injected with a corresponding volume of vehicle. After injection, ovaries were replaced and the incision closed with skin staples or sutures. At 8–72 h after surgery, the rats were killed by CO2 asphyxiation, and their ovaries were removed and placed in Kahle solution (4% formalin, 28% ethanol, and 0.34 N glacial acetic acid) for at least 24 h before embedding.



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  		FIG. 1. Effect of VEGF (A) and DES (B) on preantral follicle growth in the rat ovary. Prepubertal rats were injected with 500 ng of VEGF (n = 3) or 50 µg of DES (n = 3) under the bursa one ovary. The contralateral ovary served as a control and was injected with vehicle. The ovaries were removed after 48 h and prepared for histology. *P < 0.05

To examine the effects of exogenous estrogen on follicle growth and VEGF expression, immature female Sprague-Dawley rats were given s.c. injections of 2 mg of DES in sesame oil. Rats (n = 3 per time point) were killed by CO2 asphyxiation at 0, 8, 24, or 48 h after injection, and the ovaries were removed and placed in Kahle solution for histology. A second group (n = 5 per time point) was treated as described above, and the ovaries were snap-frozen in liquid nitrogen and stored at -80°C for subsequent VEGF protein expression by Western blot analysis. Finally, to differentiate direct versus indirect actions of estrogen on VEGF expression, rats (n = 4) were injected with 2 µg of estradiol benzoate under the bursa of one ovary, and the contralateral ovary was injected with oil. The ovaries were removed 24 h later and snap-frozen in liquid nitrogen for subsequent VEGF protein analysis by Western blot analysis.

Tissue Processing

After fixation, the ovaries were dehydrated, embedded in Paraplast (VWR Scientific, Bridgeport, NJ), serially sectioned (thickness, 10 µm), and mounted on positively charged glass microscope slides. Slides were stained using hematoxylin and eosin. Primary and secondary follicles were counted on every fifth section. Only follicles containing an oocyte were counted to avoid counting any follicle twice. Primary follicles were described as those having an intact, enlarged oocyte with a visible nucleus and a single layer of cuboidal granulosa cells. Secondary follicles were described as follicles with two or more layers of cuboidal granulosa cells. Secondary follicles were further classified as small if they contained less than four layers of granulosa cells and large if they contained four or more layers of granulosa cells. For graphical analysis, the number of follicles of a particular category (i.e., primary) in the treated ovary was divided by the corresponding number in the control ovary to obtain a percentage control value for each animal.

Western Blot Analysis

Rat ovaries were homogenized in a buffer containing 50 mM Tris (pH 7.4), 150 mM NaCl, 1% Triton X-100, 1 mM phenylmethylsulfonylfluoride, 1 mM aprotinin, and 0.1 mM leupeptin. After centrifugation at 13 000 x g for 20 min, the supernatant was removed and the protein concentration determined using the Bio-Rad DC protein assay (Bio-Rad, Hercules, CA). Each ovarian protein sample (10 µg) was boiled in the presence of 2ß-mercaptoethanol and electrophoresed in a 12% polyacrylamide gel. Following electrophoresis, gels were electrotransferred for 2 h to Hybond-C pure nitrocellulose membranes (Amersham Pharmacia, Piscataway, NJ). Membranes were then blocked in Tris-buffered saline (50 mM Tris [pH 7.4] and 150 mM NaCl) with 5% nonfat dry milk, incubated with primary antibody (rabbit polyclonal anti-VEGF165 (A-20; Santa Cruz Biotechnologies, Santa Cruz, CA) at 1 µg/ml, washed twice with blocking buffer (15 min each wash), and incubated with secondary antibody (goat anti-rabbit immunoglobulin G conjugated with horse radish peroxidase; Vector Laboratories, Burlingame, CA) at 1:2000 dilution. After washing three times with blocking buffer (15 min each wash), detection was performed using enhanced chemiluminescence Western blotting detection reagents (Amersham Pharmacia) followed by exposure to x-ray film. Films were scanned using Visioneer Paperport software (Visioneer, Inc, Pleasanton, CA), and then individual VEGF bands (23 kDa) were densitometrically analyzed using Scion Image for Windows (Scion Corporation, Worman's Mill, CT).

Statistical Analysis

Results are depicted as the mean + SEM. Potential differences in the number of follicles or VEGF protein expression between control and treated ovaries were analyzed by paired Student t-test or analysis of variance followed by a least-significant-difference test. A P value of less than 0.05 was considered to be significant for all analyses.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The objective of the first (pilot) study was to compare the effects of VEGF on preantral follicular development to the well-established effects of estrogen in the rat ovary. The results of this experiment are depicted in Figure 1. Intrabursal administration of VEGF significantly increased the number of primary and small secondary, but not of large secondary, preantral follicles in the ovary (Fig. 1A). Similarly, intrabursal administration of DES also increased the number of primary and small secondary, but not of large secondary, preantral follicles in the rat ovary (Fig. 1B). These results indicate that direct ovarian administration of VEGF increases the number of small preantral follicles in the rat ovary, similar to the well-established effects of estrogen on early follicle growth.

The time course effects of VEGF on preantral follicle growth are depicted in Figure 2. Rats were treated with intrabursal injections of 500 ng of VEGF, and the ovaries were removed 8, 24, 48, or 72 h later, processed, and analyzed as described above. The number of primary follicles was significantly increased at 48 h following intrabursal VEGF administration. The number of small secondary follicles was increased at 48 and 72 h after VEGF. The number of large secondary follicles was increased at 8 and 48 h.



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  		FIG. 2. Time course of VEGF action on preantral follicle growth in the rat ovary. Prepubertal rats were injected with 500 ng of VEGF under the bursa of one ovary. The contralateral ovary served as a control and was injected with vehicle. The ovaries were removed at 8 (n = 3), 24 (n = 2) 48 (n = 4), or 72 h (n = 3) after injection and prepared for histology. *P < 0.05

Figure 3 depicts the dose-response effects of VEGF on preantral follicle growth. Rats (n = 3–4 per group) were treated with intrabursal injections of increasing doses of VEGF (5–1000 ng) for 48 h, after which the ovaries were removed and the number of primary and secondary preantral follicles was measured. Vascular endothelial growth factor increased the number of preantral follicles in a dose-dependent manner. The lowest dose of VEGF (5 ng) was ineffective at increasing either primary or secondary follicle numbers after 48 h. The 10-ng VEGF dose resulted in a small, but significant, increase in primary, but not in secondary, follicle numbers. At all doses greater than 10 ng, VEGF significantly stimulated both primary and secondary follicle numbers, with 500 ng being the maximally effective dose.



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  		FIG. 3. Dose-response of VEGF action on preantral follicle growth in the rat ovary. Prepubertal rats (n = 4 per time point) were injected with 5–1000 ng of VEGF under the bursa of one ovary. The contralateral ovary served as a control and was injected with vehicle. The ovaries were removed 48 h after injection and prepared for histology. *P < 0.05

A second set of experiments was conducted to examine the effects of estrogen on expression of VEGF in the ovary and to determine whether the effects of estrogen on VEGF expression were associated with an increase in follicle numbers. In these experiments, immature female Sprague-Dawley rats were injected s.c. with 2 mg of DES and then killed 0, 8, 24, or 48 h after DES injection (Fig. 4). At 24 h after DES injection, the numbers of small and large secondary follicles were significantly greater (P < 0.05), and the number of primary follicles tended to be greater (P = 0.089), than control levels (0 h). At 48 h, only larger secondary follicles continued to be increased above control levels. Similarly, exogenous DES administration stimulated VEGF protein expression in the rat ovary in a time-dependent manner. As determined by Western blot analysis (Fig. 4, top), VEGF protein levels were significantly increased at 24 and 48 h following DES administration (P < 0.05).



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  		FIG. 4. Effect of DES on VEGF protein expression (top) and preantral follicle growth (bottom) in the rat ovary. Rats were injected s.c. with 2 mg of DES in oil. The ovaries were removed at 0–72 h after injection and prepared for histology (n = 3 per time point) or snap-frozen in liquid nitrogen for protein analysis (n = 5 per time point). *P < 0.05 compared to 0 h

To assess whether estrogen was increasing VEGF expression by acting directly on the ovary or perhaps indirectly, via stimulation of endocrine factors (i.e., FSH), we examined the effects of intrabursal estrogen administration on VEGF expression (Fig. 5). Intrabursal administration of estrogen resulted in a significant increase in ovarian VEGF expression, similar to the effects observed following systemic estrogen administration (P < 0.05).



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  		FIG. 5. Effect of intrabursal estradiol benzoate on VEGF protein expression in the rat ovary. Prepubertal rats were injected with 2 µg of estradiol benzoate (n = 4) under the bursa in one ovary. The contralateral ovary served as a control and was injected with vehicle. The ovaries were removed after 24 h and frozen in liquid nitrogen for protein analysis. *P < 0.05


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The data described in the present study reveal, to our knowledge for the first time, that VEGF can increase the number of preantral follicles in the rat ovary. The effect of VEGF on primary and secondary follicles was time- and dose-dependent. In addition, the increase in primary and secondary follicles elicited by VEGF was similar to that observed following estrogen treatment. Direct ovarian administration of VEGF resulted in an approximately 75%–100% increase in primary and secondary follicles in the rat ovary. These results are comparable to the 50%–70% increase in primary and secondary follicles observed after estradiol treatment.

Vascular endothelial growth factor increased the number of primary and secondary follicles within 24–48 h following administration. These data suggest that the rat ovary contains a cohort of follicles that are already sensitive to the stimulatory effects of VEGF. The more rapid increase in large secondary follicles following VEGF administration may reflect a more rapidly growing cohort of follicles compared to primary and small secondary follicles. That the number of primary follicles did not decrease when secondary follicles were increasing may suggest that the primary follicle pool was being replenished with follicles recruited from the primordial pool. Both primary and secondary follicle numbers were returning to control levels within 72 h of VEGF administration, perhaps reflecting the relatively short half-life of this angiogenic factor or that follicles were funneling into larger follicle sizes.

Vascular endothelial growth factor significantly stimulated the number of primary and secondary follicles in a dose-dependent manner, with a maximally effective dose of 500 ng. The effects of VEGF on primary as well as small and large secondary follicles were qualitatively similar across all doses. The effect of VEGF on large secondary follicles was somewhat variable, with a relatively small stimulation of 120% (not significant) in experiment one and 149% (P < 0.05) in experiment two. The lack of statistical significance in experiment one is likely because, overall, relatively fewer large secondary follicles were present in the ovaries of these animals and one animal demonstrated no increase in large secondary follicles in the treated ovary.

Vascular endothelial growth factor could increase the number of preantral follicles in the rat ovary by a variety of mechanisms. Enhanced vascularity or vascular permeability near developing follicles could increase the delivery of endocrine or paracrine factors, such as growth factors, steroids, gonadotropins, or more generally, oxygen and nutrients to the developing follicles. Increased delivery of folliculotrophic substances could result in an increase in the rate of follicular recruitment from the primordial pool (increased follicle growth) or an inhibition of follicular atresia. Alternatively, recent evidence suggests that VEGF may have direct mitogenic effects on granulosa cells in vitro and could directly stimulate follicle growth in the rat ovary [19]. Detailed experiments examining the time course of ovarian angiogenesis, vascular permeability, and follicle growth are ongoing and should help to establish the relationship between follicle growth and angiogenesis following VEGF administration.

The results of the estrogen administration experiments suggest that estrogen stimulated VEGF expression along with increasing follicle numbers. Estrogens are potent mitogens for granulosa cells in the rat and have been demonstrated to up-regulate VEGF expression in a variety of reproductive tissues [31, 32]. Moreover, the VEGF gene contains functional estrogen response elements [33]. The specific cells contributing to the increase in VEGF expression in the present study are unknown; however, other investigators have demonstrated that theca and granulosa cells are the primary cell types expressing VEGF in the ovary. Systemic estrogen could increase ovarian VEGF expression by a direct action on granulosa cells or by an indirect action through modulating gonadotropins. The time course and follicle distribution following peripheral estrogen administration were slightly different than those for intrabursal administration; therefore, potential peripheral effects cannot be ruled out. Mattioli et al. [30] were unable to demonstrate an effect of estrogen on VEGF production in vitro in the gilt; however, they did not consider these results as being conclusive. The results of the intrabursal estrogen administration experiment in the present study clearly demonstrate that estrogen can directly stimulate VEGF expression at the level of the ovary. Any potential peripheral effects of intrabursal estrogen administration would affect both ovaries, yet increased VEGF expression was clearly evident in the treated compared to the contralateral ovary. Whether the increase in VEGF expression is secondary to effects on preantral follicle growth or reflects increased VEGF expression on a per-cell basis requires further study. Nevertheless, the present results are consistent with the hypothesis that estrogen's effects on follicle growth are associated with increased VEGF expression in the rat ovary. Certainly, demonstration of a causal link between estrogen stimulation of follicle growth and increased VEGF expression requires additional studies.

In summary, direct ovarian administration of VEGF increases the number of preantral follicles in the rat ovary, similar to the well-established effects of estrogen in this system. Moreover, exogenous estrogen up-regulates VEGF expression in the ovary and enhances early follicle growth. These data suggest that VEGF may be one of the factors that participate in regulation of early follicle growth in the ovary.


   FOOTNOTES
 
1 Presented in part at the 55th Annual Meeting of the American Society for Reproductive Medicine, Toronto, Ontario, Canada, September 25–30, 1999. Back

2 Correspondence: Douglas R. Danforth, Department of Ob/Gyn, The Ohio State University, 5th Floor Means Hall, 1654 Upham Drive, Columbus, Ohio 43210. FAX: 614 688 3551; danforth.2{at}osu.edu Back

Received: 19 October 2001.

First decision: 31 October 2001.

Accepted: 2 December 2002.


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 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Neutralization of Endogenous Vascular Endothelial Growth Factor Depletes Primordial Follicles in the Mouse Ovary
Biol Reprod, February 1, 2007; 76(2): 218 - 223.
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 Biol. Reprod.Home page
J. Greenaway, P. A. Gentry, J.-J. Feige, J. LaMarre, and J. J. Petrik
Thrombospondin and Vascular Endothelial Growth Factor Are Cyclically Expressed in an Inverse Pattern During Bovine Ovarian Follicle Development
Biol Reprod, May 1, 2005; 72(5): 1071 - 1078.
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P. R. Kezele, J. M. Ague, E. Nilsson, and M. K. Skinner
Alterations in the Ovarian Transcriptome During Primordial Follicle Assembly and Development
Biol Reprod, January 1, 2005; 72(1): 241 - 255.
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 EndocrinologyHome page
J. Greenaway, K. Connor, H. G. Pedersen, B. L. Coomber, J. LaMarre, and J. Petrik
Vascular Endothelial Growth Factor and Its Receptor, Flk-1/KDR, Are Cytoprotective in the Extravascular Compartment of the Ovarian Follicle
Endocrinology, June 1, 2004; 145(6): 2896 - 2905.
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