Molecular Human Reproduction, Vol. 6, No. 11, 993-998,
November 2000
© 2000 European Society of Human Reproduction and Embryology
Ovary and oogenesis |
Changes in expression of vascular endothelial growth factor and angiopoietin-1 and -2 in the macaque corpus luteum during the menstrual cycle
1 Division of Reproductive Sciences, Oregon Regional Primate Research Center, 505 NW 185th Ave., Beaverton, OR 97006, 2 Department of Physiology and Pharmacology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97201 and 3 Center for Research on Reproduction & Women's Health, University of Pennsylvania, Philadelphia, PA, USA
Abstract
To determine the temporal expression of vascular growth factors during the lifespan of the primate corpus luteum, experiments were designed to detect mRNA for vascular endothelial growth factor (VEGF), angiopoietin (Ang)-1 and Ang-2 and to localize protein expression for VEGF in macaque luteal tissue during the menstrual cycle. Corpora lutea (n = 3–5/stage) were collected during the early (3–5 days post-luteinizing hormone surge), mid- (6–8 days), mid-late (10–12 days), and late (14–16 days) luteal phase and at menstruation (17–18 days). Reverse transcription-polymerase chain reaction products equated to cDNA for VEGF, Ang-1 and Ang-2 in all corpora lutea. VEGF mRNA levels increased (P < 0.05) from early to mid-luteal phase and declined in the late luteal phase and at menstruation. Immunostaining for VEGF was detected in the cytoplasm of steroidogenic luteal cells, with the most intense staining in the early luteal phase. Ang-1 and Ang-2 mRNA expression was low in the early to mid-luteal phase but increased (P < 0.05) at late luteal phase before declining at menstruation. These data suggest transcriptional control of VEGF, Ang-1 and Ang-2, as well as post-transcriptional control of VEGF, in macaque corpus luteum. Dynamic expression of angiogenic/angiostatic factors appears critical for development, maintenance and regression of the luteal microvasculature during the menstrual cycle.
angiogenesis/angiopoietin-1/angiopoietin-2/corpus luteum/vascular endothelial growth factor
Introduction
Recently it was postulated that dynamic interactions between two families of angiogenic/angiostatic factors, vascular endothelial growth factor (VEGF) and angiopoietins, are critical for the formation, maintenance and degeneration of the vasculature during embryological development (Hanahan, 1997
; Maisonpierre et al., 1997). Specifically, angiopoietin (Ang)-2 promotes loosening of the peri-endothelial support cell matrix that maintains vessel integrity (Maisonpierre et al., 1997), allowing VEGF to promote angiogenesis by stimulating endothelial cell proliferation and thus sprouting of new capillaries (Hanahan, 1997). Subsequently, Ang-1 aids in maturation and stabilization of these newly developed capillaries by the recruitment of peri-endothelial support cells (Hanahan, 1997; Maisonpierre et al., 1997). Further, it is proposed that in the absence of VEGF, Ang-2 promotes vessel regression by causing the complete loss of vessel structure (Maisonpierre et al., 1997). Although the relative importance of VEGF, Ang-1 and Ang-2 in embryological vascular development is apparent, it is not clear whether these factors interact in a similar manner to control physiological angiogenesis (as opposed to that in pathological situations, e.g. tumourigenesis) (Folkman and Shing, 1992) in the adult.
The ovarian vasculature, particularly that associated with the corpus luteum during its limited lifespan in the ovarian cycle, is one of the few locations where non-pathological development, maintenance and regression of vessels occurs in the adult. At ovulation, vascular elements emerge from the thecal layer of the ruptured follicle and invade the avascular granulosa cell layer establishing an extensive capillary network that nourishes the developing corpus luteum (Bassett, 1943; Reynolds et al., 1992; Koos, 1993), and assists in the maintenance of luteal function throughout its' lifespan. Conversely, the integrity of the luteal vasculature declines during the regression of the corpus luteum near the end of the menstrual cycle (Gaytan et al., 1999). This impressive cycle of neovascularization and vessel degeneration is generally believed to occur in response to local substances produced by the corpus luteum (Gospodarowicz and Thakral, 1978). Recently, considerable attention has focused on endothelial cell-specific factors (Suri et al., 1996) including VEGF (Ferrara and Davis-Smyth, 1997), Ang-1 (Davis et al., 1996) and Ang-2 (Maisonpierre et al., 1997).
Previous studies demonstrated the presence of VEGF mRNA and protein in the corpus luteum of several species (Phillips et al., 1990; Koos, 1995; Redmer and Reynolds, 1996b), including primates (Ravindranath et al., 1992; Kamat et al., 1995; Gordon et al., 1996; Hazzard et al., 1999). Also, Ang-1 and Ang-2 mRNA expression was detected in the ovary of the rat (Maisonpierre et al., 1997), cow (Goede et al., 1998) and monkey (Hazzard et al., 1999). However, information about time-specific expression of these angiogenic factors throughout the lifespan of the corpus luteum is lacking, especially in primates. Recently, we reported the dynamic expression of VEGF and the angiopoietins in the peri-ovulatory follicle following the mid-cycle gonadotrophin surge in rhesus monkeys (Hazzard et al., 1999). The objective for this study was to use the rhesus monkey to determine the temporal expression of VEGF, Ang-1 and Ang-2 by the corpus luteum throughout its lifespan in the menstrual cycle, as an initial step in considering the role of these endothelial cell-specific factors in the development, maintenance and regression of the primate corpus luteum.
Materials and methods
Animals
The general care and housing of rhesus monkeys at the Oregon Regional Primate Research Center (ORPRC) has been described previously (Wolf et al., 1990). Animal protocols and experiments were approved by the ORPRC Animal Care and Use Committee, and studies were conducted in accordance with the NIH guide for the care and use of laboratory animals. Adult female rhesus monkeys exhibiting normal menstrual cycles of ~28 days were bled daily by saphenous venipuncture beginning on days 6–8 following the onset of menses. Serum concentrations of estradiol and progesterone were measured by radioimmunoassays validated for non-human primates in the Endocrine Services Core Laboratory (Resko et al., 1975; Hess et al., 1981). Oestradiol values were used to estimate the day of the mid-cycle gonadotrophin surge and time of ovulation as previously established in our laboratory (Stouffer et al., 1994), with the exact day of the surge subsequently confirmed in an LH bioassay (VandeWeile et al., 1971). Briefly, day 1 of the luteal phase is designated as the day when preovulatory serum oestradiol concentrations (range, 250–600 pg/ml) decline to <100 pg/ml (Stouffer et al., 1994). Animals were randomly assigned for timed collection of the corpus luteum (n = 3–5 per stage of the luteal phase) during the early (3–5 days post-LH surge), mid- (6–8 days), mid–late (10–12 days), and late (14–16 days) luteal phase of the menstrual cycle, and at menstruation (17–18 days). This provided tissues at intervals representing developing, functional, on the verge of regression, regressing, and regressed corpora lutea, respectively.
Tissue preparation
Tissues were collected from anaesthetized animals (Duffy et al., 2000) via laparotomy and immediately immersed in cold phosphate-buffered saline (PBS; mmol/l: 138 NaCl, 2 KCl, 1.5 KH2PO4, 9.6 Na2HPO4; pH 7.4) and transported to the laboratory on ice. The tissue was bisected, and one portion immediately frozen in liquid N2 for RNA retrieval, and the other fixed by immersion in 4% paraformaldehyde in PBS for 18–20 h and paraffin-embedded.
RNA isolation and semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR)
Total RNA was isolated from 25–75 mg luteal tissue using the Trizol reagent (BRL, Gaithersburg, MD, USA) as per manufacturer's instructions. Quality and quantity of RNA was determined by spectrophotometry, and integrity was further checked using electrophoresis of samples in a 2% agarose gel stained with ethidium bromide. RNA samples were reverse-transcribed and subjected to PCR as previously described (Chaffin and Stouffer, 1999). This method has also been used to analyse VEGF and Ang mRNA in granulosa cells of the macaque peri-ovulatory follicle (Hazzard et al., 1999). Briefly, RNA (0.5–1.0 µg in 10 µl) was treated with RNase-free DNase I (BRL) to remove contaminating genomic DNA, before reverse transcription using 200 units of Molony Murine Leukemia Virus reverse transcriptase (MMLV; BRL).
PCR was performed using oligonucleotides synthesized by Gibco-BRL Custom Primers. Table I lists the primer sequences designed from published DNA sequences (DNASTAR, Inc., Madison, WI, USA), with the determined optimal primer concentrations used for each specific reaction. PCR reactions were performed in a 75 µl volume containing experimental + internal standard primers at optimal concentrations determined as part of the validation process, plus appropriate buffers, MgCl2, dNTPs and Taq DNA polymerase (Promega Biotech, Madison, WI, USA). Each reaction was overlaid with 40 µl of mineral oil, and placed in a thermal cycler (MJ Research, Watertown, MA, USA) for an empirically determined number of cycles of denaturing, annealing and primer extension. Aliquots of each PCR reaction (20 µl) were electrophoresed through a 2% agarose gel stained with 0.1 µg/ml ethidium bromide. Gels were visualized on a UV transilluminator and photographed using 667 Polaroid film, and the photographs were analysed by densitometry. All values were normalized to the internal standard cyclophilin mRNA; no apparent changes were observed in luteal tissue expression for the standard at any stage of the menstrual cycle (Duffy and Stouffer, 1995).
|
Validation of the RT-PCR assay was performed as described previously (Chaffin and Stouffer, 1999
), using luteal tissue collected throughout the menstrual cycle as a source of RNA (data not shown). In brief, the amount of co-amplified product for experimental and internal standard primer sets was linear and parallel with increasing amounts of cDNA, and cycle number was optimized in the exponentially increasing phase of detectable product. In order to estimate within-assay variability, total RNA from the five different collection stages of the luteal tissue (representing five monkeys) was combined and reverse transcribed as described to form a pool that was amplified as four or five replicates during each PCR with the appropriate set of primers. Within-assay variability typically ranged from <1 to 12%. Sequence analysis (performed by ORPRC Molecular Biology Core) confirmed the identity of the cDNA fragments. Homology of the cDNA fragments to the published sequences of corresponding cDNA from other species was previously demonstrated (Hazzard et al., 1999).
Immunocytochemistry for VEGF
Tissue sections (5 µm) were cut at room temperature (25°C) on an American Optical microtome (Southbridge, MA, USA) and mounted on Superfrost plus slides (Fisher, Santa Clara, CA, USA). For antigen retrieval, sections were deparaffinized in three changes of xylene for 5 min each followed by three changes of absolute ethanol (1 min each). Sections were rehydrated through a graded series of ethanol concentrations followed by water, before immersing in Tris (pH 8.0) and heat treating in a standard kitchen pressure cooker for 10 min (Santa Cruz Biotechnology, Inc., CA, USA). Sections were washed and blocked using a standard avidin-biotin peroxidase kit (Vector Laboratories, Burlingame, CA, USA) for 10 min and incubated overnight at 4°C with the primary antibody (VEGF AB#2 detecting VEGF-A, 8 µg/µl; Oncogene Research Products, Cambridge, MA, USA). The next day the sections were washed with 0.5 mol/l Tris-buffered saline (TBS) and immersed in two changes of 0.05% Tween in TBS for 5 min each. Sections were rinsed before adding a 1:200 dilution of biotinylated second antibody (Vector) and incubating for 30 min at room temperature. Slides were then rinsed before adding ABC solution (Vector) and incubating at room temperature for 30 min. Finally, after rinsing, sections were treated with liquid 0.025% diaminobenzidine tetrahydrochloride (Dojindos DAB; Wako Chemicals, Richmond, VA, USA) for 10 min and thoroughly rinsed before counterstaining. VEGF preabsorption was completed by incubating the antibody (8 µg/µl) overnight at 4°C in the presence of 10-fold excess recombinant human VEGF (R&D Systems, Inc., Minneapolis, MN, USA).
Statistical analysis
Data were subjected to a Bartlett's test, and subsequently transformed (log+2) prior to one-way analysis of variance, followed by Newman-Keuls test for means comparison. Differences were considered significant at P < 0.05 and values are presented as mean ± SEM.
Results
Figure 1 summarizes VEGF mRNA expression by the corpus luteum at specific stages of the luteal phase, and during menstruation. VEGF mRNA levels were detectable throughout the luteal phase. However, mRNA levels increased from early to mid-luteal phase (P < 0.05), and remained elevated at the mid–late luteal phase. VEGF mRNA then declined in late luteal phase and at menstruation to levels that were comparable to the early luteal phase.
|
Immunocytochemistry for VEGF protein in the macaque corpus luteum is represented in Figure 2
, as a composite of sections from the early, mid-, mid-late and late stages of the luteal phase. In all sections, brown staining represents specific staining for VEGF protein as determined by its virtual absence following either preabsorption of the VEGF antibody with VEGF (not shown), or in omission of any primary antibody (Figure 2G compared to Figure 2C). In all stages of the luteal phase, staining was detectable in the cytoplasm of the luteal (steroidogenic) cell populations. Staining along the infolding of the corpus luteum (Figure 2E) suggested that theca-lutein cells have a more heterogeneous staining pattern compared to that in the granulosa-lutein cells in the luteal parenchyma. Although no apparent specific staining was detected in endothelial or other cell populations within the corpus luteum, staining was observed in the vascular cells of the small vessels in the ovarian stroma, surrounding the corpus luteum (Figure 2F). Intense staining for VEGF protein was observed in the luteinizing cells at early luteal phase (Figure 2A). Staining for VEGF protein declined in the large luteal cells by mid–late and late luteal phase (Figure 2C and D respectively).
|
Angiopoietin mRNA expression (Figure 3
) was also apparent in corpora lutea throughout the menstrual cycle. Ang-1 mRNA levels tended to increase from early to mid–late luteal phase, but unlike VEGF mRNA did not peak (P < 0.05) until the late luteal phase where levels were 6-fold higher than the early luteal phase (Figure 3A). Ang-2 mRNA levels (Figure 3B) remained low throughout the luteal phase until transiently increasing (6-fold; P < 0.05) in the late luteal phase. By the time of menstruation, Ang-1 and Ang-2 mRNA returned to concentrations similar to those in the early luteal phase.
|
Discussion
This is the first report demonstrating VEGF mRNA and protein expression in the primate corpus luteum at specific stages throughout the luteal phase, corresponding to the developing (early), functional (mid-), onset of regression (mid–late) and regressing (late) corpus luteum, as well as regressed tissue (menstruation). Although VEGF mRNA and protein expression were detectable during each stage of the luteal phase, different patterns of expression were observed. Peak expression of VEGF mRNA occurred in the mid- to mid-late luteal phase before expression declined in the late luteal phase and at menses. Similarly, VEGF mRNA has been detected in the macaque corpus luteum using Northern hybridization, in which multiple bands hybridized for VEGF, and expression was reportedly maximal in the mid- to mid–late luteal phase (Ravindranath et al., 1992). However, temporal VEGF mRNA expression may be species-dependent, as peak expression was observed in the ovine corpus luteum during the early luteal phase (Redmer et al., 1996a). VEGF protein expression also appeared to vary during the luteal phase. Although the immunocytochemistry data are not quantitative, the most intense cytoplasmic staining for VEGF was observed during the early stage of corpus luteum development, as well as in the functional corpus luteum at mid-luteal phase. However, staining intensity for VEGF declined with the onset of regression (mid–late), and continued to drop during corpus luteum regression. Although we cannot rule out that cell size may account for the differences in early luteal VEGF expression, these data support the observations of others that the most intense staining for VEGF occurs in the early corpus luteum of humans (Kamat et al., 1995) and sheep (Redmer and Reynolds, 1996b), with more variable staining in the mid-luteal phase of humans (Kamat et al., 1995; Gordon et al., 1996), and less intense staining in the late ovine corpus luteum (Redmer and Reynolds, 1996b). Further, VEGF protein concentrations in luteal extracts from human ovaries were highest in the early and mid-luteal phases and decreased in the late luteal phase (Otani et al., 1999). Interestingly, although the most intense staining for VEGF was in the early luteal stage, peak mRNA expression occurred in the mid- to mid–late corpus luteum. Although mRNA or protein stability and turnover were not examined here, we recently observed a similar divergence in VEGF mRNA and protein expression in the peri-ovulatory follicle as well (Hazzard et al., 1999), suggesting post-transcriptional regulation of VEGF in the luteal phase. Collectively, these data are consistent with a local role for VEGF in development and maintenance of the corpus luteum in primates (Ravindranath et al., 1992; Kamat et al., 1995; Gordon et al., 1996) and other species (Koos, 1995; Redmer and Reynolds, 1996b), which may diminish at the time of luteolysis.
Cytoplasmic staining for VEGF appears compartmentalized within the primate corpus luteum. Vascular and connective tissue cells, which account for ~50% of the cell types that make up the corpus luteum (Dharmarajan et al., 1985), did not stain for VEGF, while intense staining for VEGF occurred in the steroidogenic cell populations in the corpus luteum. Interestingly, granulosa lutein cells stained uniformly in the early to mid-luteal phase while putative theca lutein cells displayed a more heterogenous staining pattern. However, co-localization of VEGF and the steroidogenic enzyme P450C17 are needed to definitively examine VEGF in theca lutein cells (Sanders and Stouffer, 1996). These data support the observations by others that there is less intense staining of the theca-lutein cell population compared to the granulosa-lutein cells (Kamat et al., 1995; Gordon et al., 1996). Nevertheless, the steroidogenic cells of the corpus luteum appear to be the sites of VEGF production (Christenson and Stouffer, 1997), while VEGF receptors are found on the endothelial cell population (Ferrara and Davis-Smyth, 1997; Neufeld et al., 1999). One might expect endothelial cell staining for VEGF because of receptor uptake; however, endothelial cell staining may be difficult to detect due to the intense background of granulosa-lutein cell staining. Remarkably, VEGF staining was apparent around the small vessels in the stroma of the ovary, reflecting either receptor uptake or possibly endothelial cell production of VEGF (Nomura et al., 1995; Nicosia et al., 1997; Yamagishi et al., 1997). However, further studies are needed to address whether primate ovarian endothelial cells are expressing or binding VEGF.
This is also the first report on Ang-1 and Ang-2 expression (mRNA) in the primate corpus luteum throughout the luteal lifespan in the menstrual cycle. The patterns of Ang-1 and Ang-2 expression were similar during the luteal phase; low at early to mid-luteal phase with a transient peak during corpus luteum regression at late luteal phase. These data could indicate that a fairly tight link between expression of Ang-1 and its natural antagonist Ang-2 is necessary to assist in the development and regression of vasculature in the primate corpus luteum. A dramatic shift in the ratio of Ang-2 to Ang-1 expression during the lifespan of the corpus luteum in the cow has been demonstrated (Goede et al., 1998). Specifically, this ratio increased dramatically in the late luteal phase, suggesting that overexpression of Ang-2 during luteolysis could reflect the regression of capillaries. However, this may not be the case as Ang-1 and Ang-2 were suggested to exist in a local negative-feedback loop where Ang-2 mRNA expression decreased when bovine microvascular endothelial cells are incubated in the presence of Ang-1 (Mandriota and Pepper, 1998). Whether endocrine or other factors, e.g. LH/chorionic gonadotrophin or hypoxia, regulate Ang-1 or Ang-2 expression in the ovary or corpus luteum, as proposed for VEGF (Nomura et al., 1995; Redmer and Reynolds, 1996b), awaits study. Alternatively, expression of Ang-1 and Ang-2 may be compartmentalized, and vascular development or regression regulated by minimizing the interaction of these angiogenic factors. Maisonpierre et al. (1997) localized Ang-1 and Ang-2 mRNA to different areas of the mouse corpus luteum. Specifically, Ang-2 was hybridized to the front of vessels invading the developing corpus luteum, while Ang-1 appeared to follow rather than precede the ingrowth into the early corpus luteum. Further studies addressing the localization of VEGF, Ang-1, -2, and other factors (Ang-4) (Valenzuela et al., 1999) throughout the lifespan of the primate corpus luteum are warranted. To date, immunocytochemistry for Ang proteins remains to be validated in the primate corpus luteum due to the lack of specific antibodies.
Differences in the temporal expression of VEGF versus Ang-1 and Ang-2 during the lifespan of the macaque corpus luteum are consistent with the embryological model suggesting that a balance of these factors may control angiogenesis, vessel maintenance and degeneration (Hanahan, 1997; Maisonpierre et al., 1997). In our study, the dominant presence of VEGF in the early corpus luteum would be assisted by low concentrations of Ang-2 and Ang-1 to cause capillary development and maturation. Continued VEGF expression in the presence of rising Ang-1 concentrations during the early to mid–late luteal phase would promote vessel maintenance which are then maintained in the mid- to mid–late corpus luteum. Subsequently, the concomitant decline in VEGF expression with an increase in Ang-1 and Ang-2 expression in the late luteal phase, would promote vessel regression that contributes to the demise of the corpus luteum. Although we cannot rule out that other factors may be involved, the current results extend the concepts of this model based on embryonic angiogenesis to include vascular events during the lifespan of the corpus luteum during the reproductive cycle in adults. However, additional studies are needed to define the spatial expression and action of these local factors in the primate corpus luteum.
In summary, rhesus monkeys exhibiting normal menstrual cycles were used to reveal the presence of angiogenic/ angiostatic factors in the corpus luteum. VEGF, Ang-1 and Ang-2 mRNA were detected throughout the lifespan of the corpus luteum, but displayed different patterns of expression across the luteal phase. VEGF mRNA and protein were in high abundance early to mid-luteal phase, while Ang-1 and Ang-2 mRNA expression increased in the late luteal phase. We interpret the pattern of expression along with the proposed function of these factors (Maisonpierre et al., 1997) to represent a dynamic interaction that could be critical for the development, maintenance and eventual regression of the capillary blood supply in the primate corpus luteum during the menstrual cycle.
Acknowledgments
The authors thank the Division of Animal Resources, the Endocrine Services Core, the Molecular Biology Core, the Imaging and Morphology Core Laboratories and the surgical team of Dr John Fanton for their technical expertise and services. This research was supported by NICHD/NIH through cooperative agreement (U54-18185, HD22408, HD07133 and RR00163) as part of the Specialized Cooperative Centers Program in Reproduction Research.
Notes
4 To whom correspondence should be addressed at: Division of Reproductive Sciences, Oregon Regional Primate Research Center, 505 NW 185th Ave., Beaverton, OR 97006, USA. E-mail: stouffri{at}ohsu.edu 
References
Bassett, D.L. (1943) The changes in the vascular pattern of the ovary of the albino rat during the estrus cycle. Am. J. Anat., 73, 251–291.[ISI]
Chaffin, C.L. and Stouffer, R.L. (1999) Expression of matrix metalloproteinases and their tissue inhibitor messenger ribonucleic acids in macaque periovulatory granulosa cells: time course and steroid regulation. Biol. Reprod., 61, 14–21.
Christenson, L.K. and Stouffer, R.L. (1997) Follicle-stimulating hormone and luteinizing hormone/chorionic gonadotropin stimulation of vascular endothelial growth factor production by macaque granulosa cells from pre- and periovulatory follicles. J. Clin. Endocrinol. Metab., 82, 2135–2142.
Davis, S., Aldrich, T.H., Jones, P.F. et al. (1996) Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell, 87, 1161–1169.[ISI][Medline]
Dharmarajan, A.M., Bruce, N.W. and Meyer, G.T. (1985) Quantitative ultrastructural characteristics relating to transport between luteal cell cytoplasm and blood in the corpus luteum of the pregnant rat. Am. J. Anat., 172, 87–99.[ISI][Medline]
Duffy, D.M. and Stouffer, R.L. (1995) Progesterone receptor messenger ribonucleic acid in the primate corpus luteum during the menstrual cycle: Possible regulation by progesterone. Endocrinology, 136, 1869–1876.[Abstract]
Duffy, D.M., Chaffin, C.L. and Stouffer, R.L. (2000) Expression of estrogen receptor a and b in the rhesus monkey corpus luteum during the menstrual cycle: regulation by luteinizing hormone and progesterone. Endocrinology, 141, 1711–1717.
Ferrara, N. and Davis-Smyth, T. (1997) The biology of vascular endothelial growth factor. Endocr. Rev., 18, 4–25.
Folkman, J. and Shing, Y. (1992) Angiogenesis. J. Biol. Chem., 267, 10931–10934.
Gaytan, F., Morales, C., Garcia-Pardo, L. et al. (1999) A quantitative study of changes in the human corpus luteum microvasculature during the menstrual cycle. Biol. Reprod., 60, 914–919.
Goede, V., Schmidt, T., Kimmina, S. et al. (1998) Analysis of blood vessel maturation processes during cyclic ovarian angiogenesis. Lab. Invest., 78, 1385–1394.[ISI][Medline]
Gordon, J.D., Mesiano, S., Zaloudek, C.J. et al. (1996) Vascular endothelial growth factor localization in human ovary and fallopian tubes: Possible role in reproductive function and ovarian cyst formation. J. Clin. Endocrinol. Metab., 81, 353–359.[Abstract]
Gospodarowicz, D. and Thakral, K.K. (1978) Production of a corpus luteum angiogenic factor responsible for proliferation of capillaries and neovascularization of the corpus luteum. Proc. Natl Acad. Sci. USA, 75, 847–851.
Hanahan, D. (1997) Signaling vascular morphogenesis and maintenance. Science, 277, 48–50.
Hazzard, T.M., Molskness, T.A., Chaffin, C.L. et al. (1999) Vascular endothelial growth factor (VEGF) and angiopoietin regulation by gonadotrophin and steroids in macaque granulosa cells during the peri-ovulatory interval. Mol. Hum. Reprod., 5, 1115–1121.
Hess, D.L., Spies, H.G. and Hendrickx, A.G. (1981) Diurnal steroid patterns during gestation in the rhesus macaque: Onset, daily variation, and the effects of dexamethasone treatment. Biol. Reprod., 24, 609–616.[Abstract]
Houck, K.A., Ferrara, N., Winer, J. et al. (1991) The vascular endothelial growth factor family: Identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol. Endocrinol., 5, 1806–1814.[Abstract]
Kamat, B.R., Brown, L.F., Manseau, E.J. et al. (1995) Expression of vascular permeability factor/vascular endothelial growth factor by human granulosa and theca lutein cells. Am. J. Pathol., 146, 157–165.[Abstract]
Koos, R.D. (1993) Ovarian angiogenesis. In Adashi, E.Y. and Leung, P.C.K. (eds), The Ovary. Raven Press, New York, pp. 433–453.
Koos, R.D. (1995) Increased expression of vascular endothelial growth/permeability factor in the rat ovary following an ovulatory gonadotropin stimulus: Potential roles in follicle rupture. Biol. Reprod., 52, 1426–1435.[Abstract]
Maisonpierre, P.C., Suri, C., Jones, P.F. et al. (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science, 277, 55–60.
Mandriota, S.J. and Pepper, M.S. (1998) Regulation of angiopoietin-2 mRNA levels in bovine microvascular endothelial cells by cytokines and hypoxia. Circ. Res., 83, 852–859.
Neufeld, G., Cohen, T., Gengrinovitch, S. et al. (1999) Vascular endothelial growth factor (VEGF) and its receptors. FASEB J., 13, 9–22.
Nicosia, R.F., Lin, Y.J., Hazelton, D. et al. (1997) Endogenous regulation of angiogenesis in the rat aorta model. Role of vascular endothelial growth factor. Am. J. Pathol., 151, 1379–1386.[Abstract]
Nomura, M., Yamagishi, S., Harada, S. et al. (1995) Possible participation of autocrine and paracrine vascular endothelial growth factors in hypoxia-induced proliferation of endothelial cells and pericytes. J. Biol. Chem., 270, 28316–28324.
Otani, N., Minami, S., Yamoto, M. et al. (1999) The vascular endothelial growth factor/fms-like tyrosine kinase system in human ovary during the menstrual cycle and early pregnancy. J. Clin. Endocrinol. Metab., 84, 3845–3851.
Phillips, H.S., Hains, J., Leung, D.W. et al. (1990) Vascular endothelial growth factor is expressed in rat corpus luteum. Endocrinology, 127, 965–967.[Abstract]
Ravindranath, N., Little-Ihrig, L., Phillips, H.S. et al. (1992) Vascular endothelial growth factor messenger ribonucleic acid expression in the primate ovary. Endocrinology, 131, 254–260.[Abstract]
Redmer, D.A., Dai, Y., Li, J. et al. (1996a) Characterization and expression of vascular endothelial growth factor (VEGF) in the ovine corpus luteum (CL). J. Reprod. Fertil., 108, 157–165.[Abstract]
Redmer, D.A. and Reynolds, L.P. (1996b) Angiogenesis in the ovary. Rev. Reprod., 1, 182–192.[Abstract]
Resko, J.A., Ploem, J.G. and Stadelman, H.L. (1975) Estrogens in fetal and maternal plasma of the rhesus monkey. Endocrinology, 97, 425–430.[Abstract]
Reynolds, L.P., Killilea, S.D. and Redmer, D.A. (1992) Angiogenesis in the female reproductive system. FASEB J., 6, 886–892.[Abstract]
Sanders, S.L. and Stouffer, R.L. (1996) Localization of steroidogenic enzymes in macaque luteal tissue during the menstrual cycle and simulated early pregnancy: Immunohistochemical evidence supporting the two-cell model for estrogen production in the primate corpus luteum. Biol. Reprod., 56, 1077–1087.[Abstract]
Stouffer, R.L., Dahl, K.D., Hess, D.L. et al. (1994) Systemic and intraluteal infusion of inhibin A or activin A in rhesus monkeys during the luteal phase of the menstrual cycle. Biol. Reprod., 50, 888–895.[Abstract]
Suri, C., Jones, P.F., Patan, S. et al. (1996) Requisite role of angiopoietin-1, a ligand for the Tie2 receptor, during embryonic angiogenesis. Cell, 87, 1171–1180.[ISI][Medline]
Valenzuela, D.M., Griffiths, J.A., Rojas, J. et al. (1999) Angiopoietins 3 and 4: diverging gene counterparts in mice and humans. Proc. Natl. Acad. Sci. USA, 96, 1904–1909.
VandeWeile, R.L., Bogumil, J. and Dyrenfurth, I. (1971) Mechanisms regulating the menstrual cycle in women. Recent Prog. Horm. Res., 26, 63–103.
Wolf, D.P., Thomson, J.A., Zelinski-Wooten, M.B. et al. (1990) In vitro fertilization-embryo transfer in nonhuman primates: The technique and its applications. Mol. Reprod. Dev., 27, 261–280.[ISI][Medline]
Yamagishi, S., Yonekura, H., Yamamoto, Y. et al. (1997) Advanced glycation end products-driven angioenesis in vitro. Induction of the growth and tube formation of human microvascular endothelial cells through autocrine vascular endothelial growth factor. J. Biol. Chem., 272, 8723–8730.
Submitted on May 25, 2000; accepted on August 17, 2000.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. van den Driesche, M. Myers, E. Gay, K. J. Thong, and W. C. Duncan HCG up-regulates hypoxia inducible factor-1 alpha in luteinized granulosa cells: implications for the hormonal regulation of vascular endothelial growth factor A in the human corpus luteum Mol. Hum. Reprod., August 1, 2008; 14(8): 455 - 464. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. L. Bogan, M. J. Murphy, R. L. Stouffer, and J. D. Hennebold Systematic Determination of Differential Gene Expression in the Primate Corpus Luteum during the Luteal Phase of the Menstrual Cycle Mol. Endocrinol., May 1, 2008; 22(5): 1260 - 1273. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. A Vonnahme, D. A Redmer, E. Borowczyk, J. J Bilski, J. S Luther, M. L. Johnson, L. P Reynolds, and A. T Grazul-Bilska Vascular composition, apoptosis, and expression of angiogenic factors in the corpus luteum during prostaglandin F2{alpha}-induced regression in sheep. Reproduction, June 1, 2006; 131(6): 1115 - 1126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Sugino, T. Suzuki, A. Sakata, I. Miwa, H. Asada, T. Taketani, Y. Yamagata, and H. Tamura Angiogenesis in the Human Corpus Luteum: Changes in Expression of Angiopoietins in the Corpus Luteum throughout the Menstrual Cycle and in Early Pregnancy J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6141 - 6148. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. R. Nayak, C. J. Kuo, T. A. Desai, S. J. Wiegand, B. L. Lasley, L. C. Giudice, and R. M. Brenner Expression, localization and hormonal control of angiopoietin-1 in the rhesus macaque endometrium: potential role in spiral artery growth Mol. Hum. Reprod., November 1, 2005; 11(11): 791 - 799. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Tesone, R. L. Stouffer, S. M. Borman, J. D. Hennebold, and T. A. Molskness Vascular Endothelial Growth Factor (VEGF) Production by the Monkey Corpus Luteum During the Menstrual Cycle: Isoform-Selective Messenger RNA Expression In Vivo and Hypoxia-Regulated Protein Secretion In Vitro Biol Reprod, November 1, 2005; 73(5): 927 - 934. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. M. Fraser, H. Wilson, K. D. Morris, I. Swanston, and S. J. Wiegand Vascular Endothelial Growth Factor Trap Suppresses Ovarian Function at All Stages of the Luteal Phase in the Macaque J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5811 - 5818. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Xu and R. L. Stouffer Local Delivery of Angiopoietin-2 into the Preovulatory Follicle Terminates the Menstrual Cycle in Rhesus Monkeys Biol Reprod, June 1, 2005; 72(6): 1352 - 1358. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Peluffo, K. A. Young, and R. L. Stouffer Dynamic Expression of Caspase-2, -3, -8, and -9 Proteins and Enzyme Activity, But Not Messenger Ribonucleic Acid, in the Monkey Corpus Luteum during the Menstrual Cycle J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2327 - 2335. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Young, B. Tumlinson, and R. L. Stouffer ADAMTS-1/METH-1 and TIMP-3 expression in the primate corpus luteum: divergent patterns and stage-dependent regulation during the natural menstrual cycle Mol. Hum. Reprod., August 1, 2004; 10(8): 559 - 565. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T.A. Molskness, R.L. Stouffer, K.A. Burry, M.J. Gorrill, D.M. Lee, and P.E. Patton Circulating levels of free and total vascular endothelial growth factor (VEGF)-A, soluble VEGF receptors-1 and -2, and angiogenin during ovarian stimulation in non-human primates and women Hum. Reprod., April 1, 2004; 19(4): 822 - 830. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Young and R. L. Stouffer Gonadotropin and Steroid Regulation of Matrix Metalloproteinases and Their Endogenous Tissue Inhibitors in the Developed Corpus Luteum of the Rhesus Monkey During the Menstrual Cycle Biol Reprod, January 1, 2004; 70(1): 244 - 252. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Hazzard, F. Xu, and R. L. Stouffer Injection of Soluble Vascular Endothelial Growth Factor Receptor 1 into the Preovulatory Follicle Disrupts Ovulation and Subsequent Luteal Function in Rhesus Monkeys Biol Reprod, October 1, 2002; 67(4): 1305 - 1312. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.A. Young, J.D. Hennebold, and R.L. Stouffer Dynamic expression of mRNAs and proteins for matrix metalloproteinases and their tissue inhibitors in the primate corpus luteum during the menstrual cycle Mol. Hum. Reprod., September 1, 2002; 8(9): 833 - 840. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||