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a INSERM U460, Remodelage vasculaire, CHU Xavier Bichât, 75870 Paris Cedex, France
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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VEGF, also known as vascular permeability factor, is a major regulator of endothelial cell proliferation and of angiogenesis, vasculogenesis, and capillary hyperpermeability [2,4–6] in both physiological and pathological neovascularization. Structurally, VEGF is a 40- to 45-kDa homodimer with limited sequence homology to the platelet-derived growth factor [7]. Molecular cloning of its cDNA revealed that alternative exon splicing of a single VEGF gene results in the generation of several VEGF isoforms comprising 121, 145, 165, 189, and 206 amino acids (VEGF121, VEGF145, VEGF165, VEGF189, and VEGF206, respectively) [8,9]. VEGF is up-regulated by hypoxia and by growth factors and cytokines such as epidermal growth factor, transforming growth factor-ß (TGF-ß), and interleukin-1ß [2]. VEGF activities are mediated by two high-affinity tyrosine kinase receptors, Flt-1 (VEGFR-1) and KDR/Flk-1 (VEGFR-2) [10–13], which are regulated by hypoxia and by growth factors (TGF-ß, tumor necrosis factor-
), including VEGF itself, in several tissues (for reviews see [2,14]). Activation of the KDR receptor has been shown to lead to mitogenicity and morphological changes [13,15], while Flt-1 is believed to be involved in chemotaxis [16] and possibly in permeability.
The presence of VEGF mRNA and protein has been demonstrated in the human and mammalian endometrium, throughout the menstrual cycle, with an increase in the late proliferative and luteal phases [17–21], periods that correspond to angiogenesis and increase of vascular permeability [1]. Consistent with these observations in vivo, the treatment of isolated endometrial stromal and epithelial cells with estradiol (E2) significantly increases mRNA corresponding to the main VEGF 121 and VEGF 165 isoforms over the control value in a dose-dependent manner [17–19]. This induction does not appear to change significantly after the addition of progesterone [19]. In addition to its expression by glandular epithelium and stromal cells, VEGF is found in vivo in capillaries, including those that have not yet formed a lumen, and in the endothelium of a few spiral arterioles. After synthesis, VEGF diffuses into the interstitial tissue and binds to capillaries, suggesting a paracrine role of this growth factor in cyclic endometrial angiogenesis [19]. So far, the expression of VEGF receptors in the endometrium has not been described.
We carried out the present study to investigate the expression and modulation of VEGF receptors in the functionalis of the human endometrium during the menstrual cycle and to understand the role(s) of VEGF in the development and permeability variations of the endometrial vascular network. Using immunocytochemistry and computerized quantitative analysis, we describe for the first time the presence of Flt-1 and Flk-1/KDR in the endothelium of endometrial capillaries and arteries, as well as their modulation according to the phase of the cycle.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Endometrial biopsies were obtained by Cornier's pipelle suction curette from 30 cycling women (aged 27–44 yr) undergoing routine gynecological investigations [19,22]. The selected patients had no evident endocrinological problems (no evidence of luteal insufficiency, no abnormal bleeding, etc.) and normal endometrial histology; none of the patients had taken hormonal medication for at least 3 mo before surgery. Informed consent was obtained from each patient, and the project was approved by the hospital ethical board. Specimens of endometrium were obtained in the proliferative (n = 13), secretory (n = 13) and menstrual (n = 4) phases of the cycle. Endometrial dating was confirmed by independent histological examination [23]. The tissue was quickly frozen in isopentane precooled in liquid nitrogen until processing.
Immunocytochemistry
Immunological detection of VEGF receptors Flk-1/KDR and Flt-1 was performed using polyclonal rabbit antibodies, CT128 directed against Flk-1/KDR [13]) (diluted 1:400) and C-17 directed against a peptide corresponding to amino acids 1312–1328 mapping at the carboxy terminus of human Flt-1 (Santa Cruz Biotechnology, Santa Cruz, CA; diluted 1:250). These antibodies have been characterized; they do not cross-react with the other receptor or with other protein kinase receptors [13,24–25]. Two other antibodies (222 and 476; a gift from J. Plouet, Toulouse, France) raised against synthetic peptides in rabbits were used to corroborate the results. The immunocytochemical staining included overnight incubation of 6-µm-thick cold (-20°C) acetone-fixed frozen sections with the specific affinity-purified rabbit polyclonal primary antibody, followed by incubation with biotinylated anti-rabbit IgG and streptavidin-biotin peroxidase (Dakopatts, Glostrup, Denmark). Peroxidase reaction was performed using amino-ethylcarbazole substrate (Sigma Chemical Co., St. Louis, MO) as previously described [19]. Some sections were counterstained with Mayer's hematoxylin. Each immunoreaction was performed twice in triplicate.
The following controls were performed: 1) preabsorption of anti-Flt-1 antibody for 12 h at 4°C with increasing amounts of purified recombinant Flt-1 (Santa Cruz) (1.5–30 µg antigen/ml diluted antibody); 2) omission of the first antibody; 3) incubation of tissue sections with irrelevant rabbit IgG immunoglobulins. Sections of preovulatory human ovarian follicles were used as a positive control.
Adjacent sections were incubated with markers of vascular endothelial cells: the polyclonal anti-Von Willebrand factor (vWf) antibody (Dakopatts), the anti-CD34 monoclonal antibody QBEND-10 (Immunotech, Marseille, France), and the anti-VE cadherin monoclonal antibody, as previously described [26]; a monoclonal anti-smooth -actin antibody (Sigma) was also used to identify smooth muscle cells in the vascular wall, as previously described [27]. Identification of interstitial macrophages was performed by immunostaining with the monoclonal antibody anti-CD 68 (Dakopatts).
Evaluation of immunostaining and vessel counting To determine the endometrial vascular immunoreactivity for VEGF receptors, both staining intensity and number of stained endothelial cells in the functionalis were evaluated. The relative intensity of the immunoreaction product was graded blindly by two independent observers (G.M. and M.P-A.) using a light microscope (Axiophot; Zeiss, Oberkochen, Germany) at 100x and 200x magnification for at least five high-power fields; it was estimated semiquantitatively, as previously described [19,22,26–27], on a 5-level scale as follows: -, no detectable stain; -/+, faint; +, moderate; ++, strong; +++, very intense staining. Each slide was examined at least twice by the same observer after an interval of 4 wk.
The number of stained capillaries in each section was determined after staining for VEGF receptors and identification of the areas containing the highest number of stained capillaries at low power. Individual immunostained capillary counts were performed at higher magnification (16x objective, 0.322 mm2/field) using a stereomicroscope (Orthoplan; Leitz Wetzlar GBH, Wetzlar, Germany) equipped with a color CDD video camera. Five different fields in one section were digitized by image analysis and computerized using the Histolab program (Microvision, Evry, France). Capillary quantification was based on the criteria of Weidner et al. [28]. Vessels counts were assessed blindly. The total number of capillaries in each biopsy was assessed by vessel counts in serial sections stained by anti-vWf, CD34, and cadherin antibodies performed with the same program. Values were expressed as means ± SEM. Differences between proliferative and secretory phases (excluding the hormonal deprivation periods: late luteal and menstrual phases) were tested using the Student's t-test. The ratios of capillaries stained for Flt-1 and for Flk-1/KDR versus vWf were calculated for every individual biopsy.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Flt-1 Expression in the Functionalis Endometrium during the Menstrual Cycle
Flt-1 immunoreactivity was mainly localized to endometrial vascular structures (capillaries and arterioles). No immunostaining was seen when the primary antibody was replaced by preimmune rabbit IgG (Fig. 1C). Preincubation of the anti-Flt-1 antibody with recombinant human Flt-1 significantly reduced the intensity of staining (Fig. 1B). Results are expressed in Figures 2–5 and Table 1.
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Vessels The vascular expression of Flt-1 was more important in the secretory than in the proliferative phase, in terms of both number of stained capillaries per unit area (172 ± 21 vs. 87 ± 9, respectively, P < 0.002) and intensity of labeling (Table 1).
During the proliferative phase, Flt-1 immunoreactivity was detectable in the endothelial cells of 57% of the capillaries and arterioles stained with anti-vWf antibody and in 47% of CD34-positive vascular structures (Table 1). In the early-mid proliferative phase (Day 5), most of the labeled vessels were capillary strands that had not yet formed a lumen composed of elongated endothelial cells (Fig. 2A). Their presence was assessed by immunolabeling of serial tissue sections with several specific endothelial markers, the anti-vWf (Fig. 2B) and the anti-CD34 [26] and anti-cadherin antibodies (not shown). The intensity of the capillary-associated immunostaining increased at the end of the proliferative phase (Day 13) (Fig. 2D and F), when immunolabeling was observed both on narrow capillaries and on capillaries with a dilated lumen (Fig. 2H). The endothelium of a limited number of arterioles was lightly labeled throughout the proliferative phase (not shown).
During the secretory period (early-mid), there was a 2-fold increase in the number of Flt-1-positive capillary strands and fully constituted capillaries versus the number during the proliferative period (172 ± 21 vs. 87 ± 9, respectively; P < 0.002) (Fig. 3 and Table 1). However, a similar increase in the number of vWf-expressing vascular structures was also present (312 ± 16 vs. 179 ± 33, respectively, P < 0.005), and consequently the ratio of Flt-1-positive capillaries to vWf-positive capillaries was not significantly different between the two phases of the cycle (0.55 ± 0.22 vs. 0.57 ± 0.23; P < 0.002), with the exception of the late secretory phase. In the midsecretory period (Days 20–24), a rich vascular network comprising about 60% of the capillary strands and fully formed capillaries expressed Flt-1 (Fig. 3C), along with the endothelium of several spiral arterioles. In the late secretory phase around Day 26 (Fig. 3E), there was a striking increase in the immunolabeling intensity; 20% of the Flt-1-positive capillaries exhibited a dilated lumen on Day 28 (Fig. 3E).
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In the menstrual phase, the immunostaining intensity for Flt-1 on capillaries decreased visibly (Fig. 4A), as did the number of stained capillaries (Table 1).
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Expression of Flt-1 on nonvascular structures In addition to the findings in endothelial cells, we observed a light Flt-1 immunolabeling on interstitial and epithelial cells (Fig. 5). This labeling decreased strongly after preincubation of the anti-Flt-1 antibody with recombinant human Flt-1 [19]. The presence of Flt-1 transcripts in isolated endometrial stromal cells was confirmed using semiquantitative reverse transcription-polymerase chain reaction (not shown).
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Interstitial cells with a round shape, a central nucleus, and the general appearance and CD 68-positive phenotype of cells of the monocyte-macrophage lineage were also immunoreactive for Flt-1 at the end of the secretory period (Days 26–28) (Fig 3E). Macrophages were numerous in the menstrual period (Fig. 5D) Their distribution during the first 2 days of menses was heterogeneous, and they were grouped in small clusters at the end of menstruation; these cells, which secrete VEGF [18], moderately expressed Flt-1 receptors (Fig. 5E). During the menstrual cycle, glandular epithelial cells were faintly immunolabeled, especially on the apical side (Fig. 5B), particularly on Days 5 to 8 (Fig. 2A) and in the mid and late secretory period (Fig. 4B).
Flk-1/KDR Expression in the Functionalis Endometrium During the Menstrual Cycle
Flk-1/KDR was mainly localized to endometrial vascular structures (capillaries and arterioles). No immunolabeling was seen when the primary antibody was replaced by preimmune rabbit IgG. Results are expressed in Figures 2–5 and Table 1.
Vessels Flk-1/KDR vascular immunoreactivity was maximal during the proliferative phase, as shown by the higher number of stained capillaries (mean 216 ± 14 in the proliferative phase vs. 175 ± 16 in the secretory phase, P < 0.05) and the higher mean ratio of Flk-1/KDR-positive to vWf-positive capillaries in this period (Table 1).
During the proliferative phase, Flk-1/KDR expression was stronger than Flt-1 expression (Table 1). At the beginning of the proliferative phase, the majority of capillary strands and several arteriolar sections were labeled with the antibody against Flk-1/KDR; the totality of the vascular structures was immunostained in the mid-late proliferative phase (Fig. 2C and Table 1). These capillaries could be identified with anti-CD34 and anti-cadherin antibodies (ratio for Flk-1/CD34 and Flk-1/cadherin: 1) and vWf antibodies (ratio Flk-1/vWf: 1.26). The intensity of Flk-1 staining persisted during the late proliferative phase (Fig. 2E, G).
In the secretory phase, a vascular immunoreactivity for Flk-1/KDR was still observed; however, while the total number of Flk-1-positive vessels was only slightly diminished (about 20%), the proportion of vessels expressing the receptor was considerably smaller (ratio 0.55 ± 0.2 vs. 1.26 ± 0.4 in the proliferative phase, P < 0.001) (Table 1) owing to the overall increase in endometrial vascular density, as assessed by quantification of vascular structures with endothelial markers. The number and proportion of capillaries stained for Flk-1/KDR and for Flt-1 were therefore similar during the same period (Table 1). The intensity of the immunolabeling was heterogeneous; it was lower in the early secretory phase (Fig. 3B), increased strongly in the midsecretory phase (Fig. 3D) (during which it was also observed in the arteriolar endothelium), and decreased again during the late luteal phase (Fig. 3F).
At the beginning of the menstrual phase (Days 1–2), only a few capillaries and some arterioles faintly expressed Flk-1/KDR. These structures were more intensely immunolabeled on Days 3–5 (Fig. 4C).
Expression of Flk-1 on nonvascular structures Light labeling of interstitial-stromal cells and of glandular epithelium was also observed at some specific stages of the cycle. No significant labeling was found in the interstitial cells during the entire proliferative period and in the early and midsecretory phases (Fig. 3B); some intensely stained cells appeared, however, in the late secretory phase (Fig. 5C). Particularly striking was the immunolabeling of numerous interstitial cells, some of which had the appearance and immunophenotype (CD68) of migratory inflammatory cells on Days 1–2 (Fig. 5F). The glandular epithelium was labeled with the anti-Flk-1 antibody, with an accentuation of the staining in the basal portion (Fig. 5C), particularly at Days 5–7, during the peri-ovulatory and midluteal periods (Figs. 2C, E and 3D) and in the menstrual phase (Fig. 4B).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Immunoreactivity for VEGF receptors is always present in vessels of the human endometrial functionalis, with variations of intensity and number of stained capillaries related to the phase of the cycle (Table 1). Specificity of the immunostaining was confirmed by the use of two different polyclonal antibodies for each receptor on serial sections of the same biopsy with comparable results, as well as by antibody absorption controls for Flt-1. The main findings of our study were that Flk-1/KDR immunoreactivity was highest during the proliferative phase and to a lesser extent during the midsecretory period, and that immunostaining for Flt-1 was maximal during the secretory phase.
During the proliferative phase, vascular expression of VEGF receptor Flk-1/KDR was high, in terms of both staining intensity and number of stained capillaries; Flk-1/KDR expression was stronger (with about 2-fold the number of stained capillaries) than Flt-1 expression during the same period. Up-regulation of Flk-1/KDR and of VEGF is observed in many pathological conditions under which angiogenesis is induced, especially in proliferating tissues (for reviews see [2,14]). VEGF has been shown to stimulate endothelial cell mitogenicity via Flk-1/KDR [13,15]. The enhanced expression of Flk-1/KDR, and to a lesser extent Flt-1, at the beginning of and during the proliferative phase, characterized by tissular growth, may account for the rapid capillary proliferation associated with regeneration following menstrual shedding [1,29]. In the late proliferative phase, a period characterized by VEGF increase [18,19], edema, and vascular hyperpermeability [1], we observe an increase in the staining intensity of Flt-1 in dilated capillaries, associated with high levels of expression of Flk-1 and of their common ligand VEGF [19]. These observations are significant because VEGF is one of the most potent stimulators of microvascular permeability known [6,30], and the increase in VEGF after E2 administration immediately precedes the increase in water imbibition and edema in the rat uterus [20]. Those findings suggest that the vascular hyperpermeability typical of this period could be mediated through the increased production of VEGF and its subsequent binding to the specific capillary receptors.
During the secretory phase, both the level of staining intensity for Flt-1 and the number of stained capillaries (about a 2-fold increase) were higher than in the proliferative phase. These findings contrast with the simultaneous decrease, of about 20%, in the number of capillaries stained for Flk-1/KDR. Progression of the functionalis from the proliferative to the secretory stage was also associated with a 2-fold increase in vascular density, resulting in no change in the proportion of Flt-1-stained capillaries (ratio 0.55 in the secretory vs. 0.57 in the proliferative phase, P < 0.002) but a decrease in the proportion of Flk-1/KDR-stained capillaries (ratio 0.55 in the secretory vs. 1.26 in the proliferative phase; P < 0.001). These findings, associated with a stronger staining intensity for both receptors and the higher binding affinity of VEGF for Flt-1 than for Flk-1 [2], suggest that the Flt-1 receptor could also be important in mediating VEGF action during the secretory phase. This particular period of the cycle is characterized by a high microvascular density (see Table 1) and by an increase in vascular permeability; these characteristics, associated with angiogenesis, are a prerequisite for predecidualization under the sequential influence of estrogens and progesterone [1]. Our observations complete previous results on the increase of VEGF and VEGF receptors about the periimplantation period, as observed in mice and rabbits by in situ hybridization for VEGF receptor mRNA [2,31,32].
The increase in Flt-1 immunoreactivity associated with a decreased expression of Flk-1/KDR at the beginning of the premenstrual period (Day 26), evidenced by strong differences in their respective staining intensities, might account for the premenstrual increase in vascular permeability, resulting in edema and in extravasation of polymorphonuclear neutrophils. Also, the presence of clusters of CD68-positive inflammatory cells both expressing high levels of VEGF receptors and capable of VEGF production [33,34] in the late luteal and menstrual phases is a new finding, which suggests an autocrine action of VEGF on these cells. The expression of Flt-1 on cells of the monocyte-macrophage lineage during these periods could imply chemotaxis of these cells [16] and their participation in the VEGF-mediated endometrial vascular changes. Hyperpermeability, subsequent edema, and the extravasation of inflammatory cells in endometrial interstitium may explain some of the premenstrual endometrial changes.
Our findings of a cyclic pattern of expression of VEGF receptors and their ligand [17–19,21] in the endometrium are not surprising, considering the need for additional vasculature constantly imposed by the cyclic evolution of the transient endometrial structures [1,29]. E2 has been shown to modulate VEGF expression in vivo and in vitro [17–19]. The cyclic changes in Flt-1 and Flk-1 expression during the menstrual cycle support a role for VEGF, and for E2 or E2+progesterone, in modulating their expression. However, the regulatory mechanisms involved are still unclear. Hypoxia, VEGF itself, and TGF-ß are known to influence expression of VEGF receptors in the vasculature [33,35–39]. Our own observations (unpublished results) suggest a direct action of E2 on VEGF receptor expression in endothelial cells in vitro. E2-induced up-regulation of Flk-1/KDR in retinal epithelial cells has also been recently suggested [40]. However, no consensus sequence for estrogen- or progesterone-responsive elements has been identified on the promoter regions of Flk-1 and Flt-1 [41,42]. Therefore, the possible roles of E2, progesterone, and VEGF itself in VEGF receptor regulation await further investigation.
The majority of published studies have described the expression of VEGF receptors in endothelial cells. However, recent studies have indicated the presence of these receptors in different cell types including epithelial cells [43], uterine smooth muscle cells [44], monocytes [16], osteoblasts [45], and tumoral cell lines [46–48]. A choriocarcinoma cell line and human retinal pigment epithelial cells in culture expressing Flt-1 and Flk-1/KDR proliferate in response to VEGF [43,49]. In the uterus, myometrial cells ([44]; and our unpublished results) and epithelial and stromal cells also express VEGF receptors, as shown by immunocytochemistry. Our data showing changes in distribution (apical or basal) and in staining intensity for VEGF receptors in glandular epithelium during the menstrual cycle suggest cyclical autocrine and paracrine effects of this growth factor at the glandular level; however, their precise extent and significance will require further investigation.
In conclusion, we have demonstrated that uterine endothelial cells express VEGF receptors Flt-1 and Flk-1/KDR in vivo in a stage-dependent cyclic fashion; their precise regulation will require further study. Our data confirm that VEGF and its receptors play an important role in endometrial angiogenesis, in hormone-dependent vascular growth, and in the increase of microvascular permeability associated with endometrial repair. Disruption of the balance between VEGF and its receptors, especially at the crucial moment of implantation, could result in defective trophoblast development. The preferential expression of Flt-1 receptors on endothelial cells in the premenstrual period when ovarian steroids are at low levels could be a prerequisite for menstrual shedding; an imbalance between VEGF and its receptors could also be involved in abnormal uterine bleeding.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported by the Institut National de la Santé et de la Recherche Médicale, The Centre National de la Recherche Scientifique, The Fondation pour la Recherche Médicale, and the Association pour la Recherche sur le Cancer. Results were presented, in part, at the Satellite Symposium "Progesterone, Progestins and Antiprogestins in the Next Millenium" of the Sixth International Congress on Hormones and Cancer, Jerusalem, Israel, 31 August–3 September 1999. 
2 Correspondence: M. Perrot-Applanat, INSERM U460, CHU Xavier Bichât, 16 Rue Henri Huchart, 75870 Paris Cedex, France. Fax: 33 1 44 85 61 56; applanat{at}bichat.inserm.fr
Accepted: September 27, 1999.
Received: February 22, 1999.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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B. Moller, C. Rasmussen, B. Lindblom, and M. Olovsson Expression of the angiogenic growth factors VEGF, FGF-2, EGF and their receptors in normal human endometrium during the menstrual cycle Mol. Hum. Reprod., January 1, 2001; 7(1): 65 - 72. [Abstract] [Full Text] [PDF]
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N. R. Nayak, H. O. D. Critchley, O. D. Slayden, A. Menrad, K. Chwalisz, D. T. Baird, and R. M. Brenner Progesterone Withdrawal Up-Regulates Vascular Endothelial Growth Factor Receptor Type 2 in the Superficial Zone Stroma of the Human and Macaque Endometrium: Potential Relevance to Menstruation J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3442 - 3452. [Abstract] [Full Text]
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L.L. Nikitenko, I.Z. MacKenzie, M.C.P. Rees, and R. Bicknell Adrenomedullin is an autocrine regulator of endothelial growth in human endometrium Mol. Hum. Reprod., September 1, 2000; 6(9): 811 - 819. [Abstract] [Full Text] [PDF]
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M. Ancelin, H. Buteau-Lozano, G. Meduri, M. Osborne-Pellegrin, S. Sordello, J. Plouet, and M. Perrot-Applanat A dynamic shift of VEGF isoforms with a transient and selective progesterone-induced expression of VEGF189 regulates angiogenesis and vascular permeability in human uterus PNAS, April 30, 2002; 99(9): 6023 - 6028. [Abstract] [Full Text] [PDF]
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