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BOR - Papers in Press, published online ahead of print October 30, 2002.
Biol Reprod 2002, 10.1095/biolreprod.102.008284
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BIOLOGY OF REPRODUCTION 68, 1107–1111 (2003)
DOI: 10.1095/biolreprod.102.008284
© 2003 by the Society for the Study of Reproduction, Inc.

Male Reproductive Tract

Endothelial Cell Proliferation in Male Reproductive Organs of Adult Rat Is High and Regulated by Testicular Factors1

Ingela Franck Lissbranta,b, Erik Lissbranta,b, Anette Perssona, Jan-Erik Damberb, and Anders Bergh2,a

a Department of Medical Biosciences, Pathology, Umeå University, 901 87 Umeå, Sweden b Department of Urology, Sahlgrenska University Hospital, 413 45 Göteborg, Sweden


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Endothelial cells in the intact adult are, apart from those in the female reproductive organs, believed to be quiescent. Systematic examination of endothelial cell proliferation in male reproductive organs has not been performed and was therefore the aim of the present study. Intact adult rats were either pulse labeled or long-term labeled with bromodeoxyuridine to label proliferating cells. The roles of Leydig cells and testosterone were examined after castration or treatment with the Leydig cell toxin ethane dimethane sulfonate (EDS) and testosterone substitution. After perfusion fixation, all blood vessels remained open and were easily identified. In all male reproductive organs studied, particularly in the testis and epididymis, endothelial cell proliferation was considerably higher than in other tissues such as the liver, brain, and muscle. Proliferating endothelial cells were observed in all types of blood vessels in male reproductive organs, but other characteristics of new blood vessel formation were not seen. High endothelial cell proliferation may reflect a continuous high turnover of endothelial cells rather than classical angiogenesis. In the epididymis, the ventral and dorsolateral prostate lobes, and the seminal vesicles, endothelial cell proliferation decreased after testosterone withdrawal and increased following testosterone treatment. In the testis, endothelial cell proliferation was decreased after Leydig cell depletion but remained low after testosterone substitution. High, hormonally regulated endothelial cell proliferation is not unique to the female but is also seen in the male reproductive organs.

epididymis, prostate, seminal vesicles, testis, testosterone


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Under normal physiological conditions, endothelial cells are believed to be quiescent in the adult, other than in the female reproductive tract and during wound healing. In contrast, 1–30% of the endothelial cells in malignant tumors proliferate [1, 2]. Because of this large difference in endothelial cell proliferation, antiangiogenic treatment aimed at proliferating endothelial cells is thought to be without major side effects. Antiangiogenic treatment does, however, induce female infertility by inhibiting the normally high endothelial cell proliferation in ovarian and endometrial tissue [3, 4]. Studies designed to systematically investigate endothelial cell proliferation in normal tissues have been few and have apparently not included the male reproductive organs. Moreover, previous studies were all performed on immersion-fixed material [1, 5, 6]. This method of fixation may result in underestimation of endothelial cell proliferation because blood vessels, particularly the smaller ones (i.e., capillaries and venules), collapse in immersion-fixed tissue and thus are not recognized as blood vessels [7, 8]. Moreover, capillaries and venules constitute the major portion of the total vascular surface area, and their endothelial cells apparently have a higher proliferation rate than those in larger vessels [1, 9]. Perfusion fixation, however, leaves the majority of vessels patent, thereby facilitating the detection of small blood vessels and their endothelial cells [8].

Recent data suggest that endothelial cell proliferation may be relatively high in the rat testis and prostate compared with other organs in the body and that endothelial cell proliferation plays an important role in hormone-induced prostate growth [10–13]. The functional significance of endothelial cell proliferation in the male reproductive tract and the mechanism of its regulation is unknown. However, the testis, prostate, epididymis, and seminal vesicle all contain a variety of potent vasoactive and angiogenic factors under normal conditions, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor, transforming growth factor ß, and their corresponding receptors [10, 12, 14–18]. VEGF has a potent effect on the vasculature in the epididymis by increasing permeability, and because it acts as a mitogen and a survival factor for endothelial cells in other organs [15, 19], it may play a similar role in the male reproductive tract.

In female reproductive tissues, VEGF levels, angiogenesis, and endothelial cell proliferation seem to be hormonally regulated [20]. It is not known whether the same is true in male reproductive organs, but recent data suggest that endothelial cell proliferation in at least the prostate and testis could be regulated by testicular hormones. In the ventral prostate of rats, endothelial cell proliferation decreases after castration and increases with testosterone supplementation [11, 13]. Furthermore, endothelial cell proliferation in the testis is regulated by a Leydig cell factor; hCG treatment increases and Leydig cell depletion decreases endothelial cell proliferation [10]. These observations prompted us to examine endothelial cell proliferation in all major male reproductive organs and to examine whether this proliferation could be hormonally regulated from the testis.


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

Male Sprague-Dawley rats (Möllegård, Denmark) approximately 3 mo of age with body weights of 350–400 g were housed in a controlled environment (12L:12D) with food and water provided ad libitum. Rats were divided into six groups: 1) intact rats injected 1 h prior to perfusion fixation with bromodeoxyuridine (BrdU, 50 mg/kg i.p.; Sigma, St. Louis, MO), a thymidine analogue that is incorporated into the DNA in the S-phase of the cell cycle [21] (pulse labeled group); 2) intact rats injected with BrdU daily for 5 days prior to perfusion fixation (long-term labeled group); 3 and 4) rats castrated via the scrotal route under pentobarbital anesthesia (50–60 mg/kg, Mebumal Vet; Nordvacc, , Hägersten, Sweden) leaving the epididymis intact and then treated with testosterone (10 mg kg body weight- day-, Sustanon; Organon, Oss, the Netherlands) or vehicle for 7 days; and 5 and 6) rats injected with a single i.p. injection of ethane dimethane sulfonate (EDS, 75 mg/kg body weight) [22] to deplete Leydig cells in the testis and then treated with vehicle or testosterone (10 mg/kg body weight- day-) for 7 days. Intact rats injected with a single dose of BrdU or with a daily dose of BrdU for 5 days and examined 1 h after the last dose were anesthetized with pentobarbital and perfusion fixed for 45 min with 4% formaldehyde solution via a cannula inserted in the left ventricle of the heart (pressure 1.3 m H20). In intact pulse-labeled or long-term-labeled rats, the following organs were removed for examination: brain, lung, heart, liver, thyroid, kidney, psoas muscle, pancreas, jejunum, adrenal gland, salivary gland, testis, epididymis, ventral and dorsolateral prostate, and seminal vesicle. Tissues were then immersion fixed for 2 h in the same fixative, dehydrated, and embedded in paraffin or glycolmethacrylate resin (Technovit 8100; Heraeus Kulzer, Werheim, Germany). The surgically castrated or EDS-treated rats (groups 3–6) were injected with BrdU (1 h labeling) and perfusion fixed 7 days after androgen withdrawal. Thereafter, the testes (EDS-treated rats), epididymis, ventral and dorsolateral prostate, and the seminal vesicles were carefully removed. As a positive control for BrdU uptake and labeling of proliferating cells, the presence of numerous labeled cells was verified in the spermatogenic and intestinal epithelia. The design of this study was approved by the local animal ethical committee in Umeå, Sweden.

Immunohistochemistry

Four-micrometer-thick paraffin-embedded sections and 1-µm-thick Technovit-embedded sections were incubated with a mouse monoclonal antibody against BrdU (1:50; DAKO, Älvsjö, Sweden) overnight followed by a biotinylated horse anti-mouse secondary antibody (1:200; Vector Laboratories, Burlingame, CA). The immunoreaction was visualized using a peroxidase-labeled avidin-biotin-complex reagent (Vectastain; Vector) with 3-amino-9-ethyl carbazole as a chromogen. The Technovit-embedded sections were used to study vascular morphology in detail, and the paraffin-embedded sections were used for measuring endothelial cell proliferation. Paraffin-embedded sections were also immunostained using a Ki-67 antibody (MIB-5; Immunotech, Marseille, France). Ki-67 antigen is expressed during all stages of the cell cycle except G0, and Ki-67 staining is commonly used to quantify cell proliferation [23]. After heating for 20 min in citrate buffer (pH 6.0), the paraffin-embedded sections were incubated overnight with the MIB-5 antibody (1:25). The immunoreaction was visualized using a CSA kit (DAKO).

Endothelial Cell Proliferation

Endothelial cell proliferation was assessed by two methods. First, the number of proliferating BrdU-labeled endothelial cells per field was assessed in a minimum of 100 visual fields in each organ at 400x magnification using a BX40 light microscope (Olympus, Tokyo, Japan) and a field size of 0.23 mm2. Based on the number of proliferating endothelial cells per field, tissues were divided into four groups. The percentage of BrdU-labeled endothelial cells was determined (labeling index of endothelial cells) in the male reproductive organs (pulse labeled, long-term labeled, surgical/EDS-treated rats) and in selected organs from each group. Between 700 and 800 endothelial cells were examined in each organ. For some organs, the percentage of Ki-67-labeled endothelial cells was also determined.

Statistical Analysis

When applicable, values are presented as means ± SD of three to six rats in each group. Groups were compared using the Mann-Whitney U-test. A P value of <0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
BrdU-labeled and unlabeled endothelial cells were easy to identify because perfusion fixation left blood vessels patent. Resting endothelial cells were flat and elongated, whereas BrdU-labeled proliferating endothelial cells were larger and more ovoid (Fig. 1). Proliferating endothelial cells were found in all types of vessels (e.g., arteries, veins, and capillaries) but were most abundant in capillaries and venules (Fig. 1).



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  		FIG. 1. Section from ventral prostate. A) Endothelial cells (arrows) labeled with BrdU for 1 h are visible in capillaries and venules (Technovit-embedded section). x400. B and C) In sections from paraffin-embedded testis (B, x400) and epididymis (C, x200) labeled with BrdU for 5 days, several BrdU-labeled endothelial cells (arrowheads) are visible within the same vessel but without any signs of sprout formation

In pulse-labeled rats (1 h BrdU labeling), organs and tissues were divided into four groups based on the number of proliferating endothelial cells per high-power (400x) visual field (Table 1). The endothelial cell labeling index (ECLI; the percentage of BrdU-labeled endothelial cells) was then assessed for representative tissues/organs in each group (Table 2). The ECLI was higher for the male reproductive organs than for other organs in the body, and the highest indices were found for the testis (2.9%) and epididymis (2.5%) (Table 2). The ECLI for the ventral and dorsolateral prostate and the seminal vesicles ranged from 1.3% to 1.9% (Table 2). In contrast, the ECLI for other organs, such as the thyroid (0.6%) and pancreas (0.5%), were <1%. Hardly any proliferating endothelial cells were found in the brain, psoas muscle, small intestine, or heart muscle, and in these organs the ECLI ranged from 0% to 0.5%. Long-term labeling of intact rats with BrdU for 5 days increased the ECLI to 2.6% in the seminal vesicles, 3.5% in the dorsolateral prostate, 4.9% in the ventral prostate, 5.6% in the epididymis, and 7.6% in the testes (Table 2). In contrast, long-term labeling of other organs resulted in few labeled endothelial cells (liver 1.6%, psoas muscle <0.1%). The labeled endothelial cells in organs from the long-term labeling experiment were sporadically distributed in the vasculature, i.e., we observed no indications of sprout formation or bridging of labeled endothelial cells.


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  		TABLE 1. Rat endothelial cell proliferation in different organs and tissues


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  		TABLE 2. ECLIa for male rat reproductive organs

EDS treatment, which effectively killed all Leydig cells in the testis, and surgical castration caused a significant decrease in endothelial cell proliferation in all male reproductive organs examined (Table 3). Testosterone supplementation for castrated or EDS-treated rats increased endothelial cell proliferation in all male reproductive organs apart from the testis, where proliferation remained low.


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  		TABLE 3. ECLIa for male reproductive organs of castrated and EDS-treated rats

To validate BrdU incorporation as a marker of cell proliferation in this study, we also examined endothelial Ki-67 expression (Fig. 2). The endothelial cell Ki-67 labeling index was considerably higher in the male reproductive organs than in the other organs examined, and it was approximately 2-fold higher than the corresponding 1-h BrdU labeling index. Quantification in the testis showed a high correlation between the BrdU and Ki-67 labeling indices (rs = 0.70, P < 0.05, n = 10). The endothelial Ki-67 labeling index was 7.0 ± 1.7 in the intact testis, and it decreased to 1.4 ± 0.8 after EDS treatment.



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  		FIG. 2. Ki-67-stained paraffin-embedded sections. A) In the intact testis, labeled endothelial cells (arrows) are visible in a venule. Spermatogonia and spermatocytes are also labeled. x250. B) In the ventral prostate, a labeled endothelial cell is visible in a venule. x625


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Endothelial cell proliferation, as evaluated by BrdU and Ki-67 labeling, was considerably higher in the male reproductive organs than in other tissues in the body, as was particularly evident in the 5-day BrdU-labeling experiments. In agreement with previous studies, in which the male reproductive organs were not examined [1, 2, 5, 6], we observed very low 1-h BrdU labeling indices in most normal tissues; this low proliferation rate was verified in the long-term labeling experiment. The endothelial cell proliferation indices observed in the male reproductive organs were, however, much lower than those in the developing corpus luteum of rats, where the 1-h labeling index has been reported as 36% [24]. However, endothelial cell proliferation in the male reproductive organs may be similar to that observed in human breast cancer, where the mean ECLI after 3–8 h of BrdU exposure was estimated as 2.2% [25]. The potential doubling times (Tpot) of endothelial cells in organs such as brain and muscle have previously been approximated to hundreds of days, whereas those in the liver, lung, and kidney were roughly estimated as 50–80 days [1]. Using the same formula and assumptions as in that study, the approximated Tpot of endothelial cells in the male reproductive organs ranged from 11 days in the testes to 24 days in the dorsolateral prostate. These results imply that the endothelial cell population in the male reproductive organs is not as static as previously believed [15].

The finding of comparatively high rates of endothelial cell proliferation in stationary organs, such as the male reproductive tract, raises several questions. Is the endothelial cell proliferation a sign of ongoing angiogenesis, or is it an isolated phenomenon, where endothelial cells are continuously replaced but the vasculature is in other ways stationary? What is the physiological significance of endothelial cell proliferation in male reproductive organs and how is it regulated? Are the male reproductive organs likely targets for long-term side effects of angiogenesis inhibitors aimed at proliferating endothelial cells, a treatment now in clinical trials for a variety of diseases such as diabetic retinopathy and cancer?

Apart from endothelial cell proliferation, we did not observe any clear signs of ongoing angiogenesis (e.g., sprout formation with labeled cells in the long-term labeling experiment or bridging of endothelial cells). Thus, endothelial cell proliferation in these organs may be isolated from other phases of blood vessel formation. Further studies are needed to elucidate this issue. The hypothesis of a continuous turnover of endothelial cells in male reproductive organs is supported by the finding of apoptotic endothelial cells in the testes under normal conditions [10] and in the prostate after castration [26].

The vasculature and endothelial cells may play a more central role in organ physiology than previously assumed. For example, in the prostate endothelial cells apparently play a role in regulation of organ size; ventral prostate endothelial cells are the first cells to go into apoptosis during castration-induced prostate involution and the first to proliferate after testosterone-stimulated prostate growth [11, 26]. Whether the vasculature plays a similar role in all testosterone-regulated organs remains to be studied.

A distinct feature especially of the testicular but also of the epididymal vasculature is a remarkably high vascular permeability [14, 27]. Because a new partially formed vessel wall may be more permeable than a fully mature differentiated and stationary one, endothelial cell proliferation may contribute to high permeability. This high permeability may be important for the formation and resorbtion of luminal fluids in the different male reproductive organs, but proliferating endothelial cells were also observed in small arteries and veins, so other roles are likely.

In the female reproductive organs, endothelial cell proliferation seems to be hormonally regulated by the gonads [4, 20]. This may also be the case in males; castration and Leydig cell depletion decreased endothelial cell proliferation and testosterone supplementation increased it, except in the testes [11, 13]. Androgen receptors have been localized in endothelial cells in the human and rat prostate and possibly also in the human testis [28–30], suggesting that androgens could have direct effects on endothelial cells. Testosterone also may stimulate the local production of endothelial cell mitogens. Because testosterone supplementation does not maintain endothelial cell proliferation in the testis, another Leydig cell factor, for example VEGF or the newly discovered endocrine gland VEGF [31], may be responsible for the high endothelial cell proliferation in this organ. VEGF, a major regulator of vessel growth and permeability, is highly expressed in several cell types in the testis, epididymis, prostate, and seminal vesicles [10, 12, 14, 15]. Furthermore, VEGF receptor 2, which mediates the mitogenic effect of VEGF on endothelial cells, is present on blood vessels in the testis, epididymis, and prostate [14, 15, 32]. VEGF expression is regulated by testosterone in the prostate, but whether this is the case in the other male sex organs remains to be studied [33].

The vasculature in the male reproductive organs may be more similar to the vasculature in the female reproductive organs than previously assumed. The endothelial cell proliferation rate is relatively high in these organs and is regulated by testicular hormones. However, the functional significance of this system remains to be elucidated.


   ACKNOWLEDGMENTS
 
Mrs. Sigrid Kilter, Mrs. Birgitta Ekblom, and Mrs. Elisabeth Dahlberg have contributed to this study by providing their skillful technical assistance.


   FOOTNOTES
 
1 This study was supported by grants from the Swedish Cancer Society, the University Hospital in Umeå, the Knut and Alice Wallenberg Foundation, the Maud and Birger Gustavsson Foundation, the Borgerskapet in Umeå Research Foundation, Gunnar, Arvid and Elisabeth Nilsson's Cancer Research Foundation, and Lion's Cancer Research Foundation, University of Umeå. Back

2 Correspondence. FAX: 46 90 7852829; anders.bergh{at}medbio.umu.se Back

Received: 10 June 2002.

First decision: 7 July 2002.

Accepted: 11 October 2002.


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 RESULTS
 DISCUSSION
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