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Endocrinology Vol. 140, No. 4 1920-1926
Copyright © 1999 by The Endocrine Society

ARTICLES

Early Effects of Castration on the Vascular System of the Rat Ventral Prostate Gland1

Ahmad Shabisgh, Nozomu Tanji, Vivette D’Agati, Martin Burchardt, Mark Rubin, Erik T. Goluboff, Daniel Heitjan, Alex Kiss and Ralph Buttyan

Departments of Urology (A.S., M.B., E.T.G., R.B.) and Pathology (N.T., V.D., M.R., R.B.), and the Division of Biostatistics (D.H., A.K.), Columbia University College of Physicians and Surgeons, New York, New York 10032

Address all correspondence and requests for reprints to: Dr. Ralph Buttyan, Department of Urology, Columbia University College of Physicians and Surgeons, Atchley Pavilion 11th Floor, 161 Fort Washington Avenue, New York, New York 10032. E-mail: rb46{at}columbia.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Recent studies have found that blood flow to the rat ventral prostate gland is drastically reduced at an early time after castration. These observations caused us to reevaluate the effects of castration on the various cell populations of the ventral prostate, especially those in the prostatic vascular system. Sections of ventral prostate glands obtained at different times after castration were analyzed using the TUNEL (terminal deoxynucleotide transferase-mediated dUTP nick END labeling) staining method to quantify apoptosis in different cell types. The results of this analysis showed a significant increase in TUNEL staining of prostate endothelial and (nonendothelial) stromal cells as early as 12 h postcastration that continued to 24 h after castration. In contrast, TUNEL labeling of prostate epithelial cells was not significantly increased compared with control values until 72 h after castration. The use of dual immunohistochemical staining procedures (anti-CD31 for endothelial cells or antismooth muscle actin for smooth muscle cells combined with TUNEL labeling) allowed us to confirm that the TUNEL-positive vascular cells at these early times after castration were endothelial in nature, whereas smooth muscle cells surrounding the prostate glands or portions of the afferent vascular endothelium were rarely TUNEL labeled. Electron microscopic evaluation of ventral prostate tissues at 48 h after castration provided further morphological evidence for the occurrence of apoptosis in prostate endothelial cells. Finally, the Lendrum-Fraser histochemical procedure used to identify fibrin leakage in tissues with vascular damage was applied to sections of the ventral prostate gland. This stain revealed diffuse fibrin accumulation in periglandular areas outside the capillaries and blood vessels in prostates from 24-h castrated rats, but not in prostates of sham-operated rats. Our results confirm an early effect of castration on the vascular system of the rat ventral prostate identified by increased apoptosis of endothelial cells and vascular leakiness. As these changes temporally precede the loss of epithelial cells, we propose that they may be causal rather than incidental to regression of the rat ventral prostate after castration.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE VENTRAL prostate gland of the rat is dependent on a continuous supply of androgenic steroids. Castration of an adult male rat will lead to the extensive regression of this tissue in association with the induction of apoptosis in the majority of ventral prostate epithelial cells (1). Recently, it was reported that a significant reduction in blood flow to the ventral prostate gland occurs early after castration (2, 3). In one report, ventral prostate blood flow was reduced by 38% at 18 h and by 48% at 24 h after castration compared with that in the ventral prostates of control-operated rats (3). In contrast, blood flow to a nonandrogen-dependent tissue (rat bladder) was not significantly changed by castration. For the ventral prostate gland, this blood flow reduction apparently precedes the appearance of apoptotic epithelial cells, thus suggesting a potential causal relationship between the androgen effects on prostate blood flow and the regression of the ventral prostate gland. Preliminary analyses of ventral prostate tissues obtained early after castration (12 h) also showed a significant increase in the number of TUNEL (terminal deoxynucleotide transferase-mediated dUTP nick END labeling)-labeled endothelial cells at this early time compared with that in normal ventral prostates (2). As the TUNEL labeling technique is used to identify cells undergoing apoptosis (4), the latter finding implies that the loss of some fraction of prostate endothelial cells by apoptosis might have some role in the corresponding reduction of prostate blood flow associated with castration.

To further examine these hypotheses, we performed a more detailed analysis of the kinetics of apoptosis in the regressing rat ventral prostate gland, especially focusing on quantifying and characterizing apoptosis in the nonepithelial cell population of the tissue. Cell loss/apoptosis during ventral prostate regression had been previously assessed quantitatively in the regressing rat ventral prostate gland by measuring DNA content in tissue or by counting visually apparent apoptotic bodies in stained tissue sections at different times after castration (5, 6). These methods do not enable the efficient discrimination of apoptosis in the nonepithelial cell elements of the prostate, and as a result, these types of cells have been virtually ignored in contemporary analyses of the effects of castration on the prostate.

Moreover, the detection of cell death/apoptosis in the nonepithelial cell population of the rat ventral prostate is also troublesome, because these cells represent such a minority of the cells in the tissue. Unlike the human prostate gland with its more extensive fibroblast and smooth muscle components, the rat ventral prostate gland is composed overwhelmingly of epithelial cells (7). The small minority of nonepithelial cells in this tissue can be distinguished as endothelial cells (making up the prostatic vasculature), smooth muscle cells (surrounding the glands and some afferent blood vessels), nerves, and nonspecific fibroblasts (with no specific cell marker other than vimentin). Given the overall abundance of epithelial cell apoptosis associated with ventral prostate regression, it is even more difficult to detect signs of apoptosis in the small areas containing nonepithelial cells in this tissue.

Based on our previous experience in the analysis of early regressing ventral prostate tissues, we hoped that the use of the contemporary TUNEL labeling techniques could help us better determine cell death/apoptosis rates in the nonepithelial cells of the rat ventral prostate gland. One advantage of this method is its ability to identify potential apoptosis in regions of nonepithelial cells where it can be especially difficult to detect the formation of apoptotic bodies. Secondly, this method can be combined with other immunohistochemical staining procedures to confirm the identify of TUNEL-positive or -negative cells. When used in conjunction with an anti-CD31 or antismooth muscle immunostaining procedure, we can verify the potential apoptosis of endothelial or smooth muscle cells that compose the prostatic vascular system.

Although TUNEL staining methods provide evidence that nuclear DNA is being degraded in individual cells, this method may not always be sufficient to confirm that the DNA degradation results from apoptosis, especially in nonepithelial cell types. Cellular morphological analysis can aid in this distinction. During apoptosis, cells readily detach from their neighbors, and their nuclear chromatin often clumps at the edges of the nucleus before pyknosis. Therefore, we have also used electron microscopic techniques to search for these characteristics in endothelial cells of the regressing ventral prostate gland.

Finally, given our focus on the potential for prostatic vascular degeneration associated with castration, we have used a histochemical staining procedure, the modified Lendrum Fraser stain (8), to analyze vascular leakiness during ventral prostate regression. This procedure allows the detection of fibrin, a serum component that is normally restricted to the vascular lumen. In some tissues, vascular degeneration is associated with increased vascular permeability that allows the fibrin to infiltrate into adjacent tissue areas. The results of these studies of the effects of castration on the vascular system of the rat ventral prostate gland have significant implications for understanding the mechanism(s) by which androgenic steroids might affect this tissue.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Experimental animals
All rats were maintained in a controlled environment with food and water available ad libitum. Upon arrival, mature male Sprague-Dawley rats (350–375 g; Charles Rivers Co., Camden, NJ) were randomized in seven groups by a computer-generated coding system. One group of animals was used as unoperated controls, and another six groups of animals were surgically castrated under anesthesia as previously described (1). The operated groups were killed at 12, 24, 48, 72, 96, and 144 h after castration by a lethal overdose of sodium pentobarbitol (100 mg/kg, ip) to obtain prostate tissues. These tissues were fixed in 10% formalin and were then dehydrated and embedded in paraffin.

TUNEL staining procedure
Fixed tissue sections (5 µM) were rehydrated and immunostained using the In Situ Cell Death Detection Kit, POD TUNEL assay (Boehringer Mannheim, Indianapolis, IN), according to the manufacturer’s specifications with the following modifications (3): nonspecific antifluorescein antibody binding was blocked by washing the slides in 1% BSA in PBS three times for 10 min each, and the slides were rinsed with PBS. The slides were then incubated with blocking solution A for 30 min and with blocking reagent B (Histomouse SP Kit, Zymed Laboratories, Inc., San Francisco, CA) for 10 min, counterstained with Harris hematoxylin for 20 sec to reveal the nuclei, mounted with glycerol gelatin, and covered with glass coverslips.

Endothelial and smooth muscle cell immunostaining
To confirm colocalization of TUNEL labeling to prostate endothelial cells we used a dual immunohistochemistry method combining the TUNEL assay with immunostaining for CD31, a specific marker for endothelial cells. Sections of ventral prostates at 12 and 24 h after castration were stained by the TUNEL technique as described. These sections were extensively rinsed in water and then incubated either with the primary mouse antihuman CD31 antibody (DAKO Corp., Carpenteria, CA) or with antismooth muscle actin (Sigma Chemical Co., St. Louis, MO) for 48 h at 4 C. After extensive washing with PBS, the sections were incubated at room temperature with a biotinylated secondary antibody (DAKO Corp. LSAB2 Kit, alkaline phosphatase, DAKO Corp.) for 3 h. Staining was completed with the standard avidin-biotin detection technique using a red substrate (Fast Red TR/Napthol AS-MX, Sigma Chemical Co.) followed by counterstaining with Harris hematoxylin for 10 sec.

Histological and statistical analysis
Light microscopic analysis allowed us to distinguish the different prostatic cell types and identify TUNEL-labeled nuclei (apoptotic cells) in sections of rat ventral prostate tissues obtained at various times after castration. Epithelial cells were extremely abundant on the sections, and TUNEL-labeled (epithelial cell) nuclei were counted in 10 different high power fields (x400) for each animal and compared to the total number of epithelial cells in the field to obtain a percentage of TUNEL-positive epithelial cells for each time point.

Endothelial and stromal cells were far less abundant. Therefore, we counted TUNEL-labeled endothelial or (nonendothelial) stromal cells in an entire section and compared these to the total number of endothelial cells/stromal cells present on the section to obtain the percentage of TUNEL-positive endothelial cells and the percentage of TUNEL-positive stromal cells for each time point.

These rates were then transformed by means of an arcsine transformation for purposes of statistical analysis. The transformed rates were used in an ANOVA to ascertain the differences between- and within-cell types across the various time points. Rates are expressed as the mean ± SE.

Transmission electron microscopic analysis for endothelial cell apoptosis
Specimens of the ventral prostate were obtained at 36 h (n = 3) and 48 h (n = 3) after castration and from unoperated controls (n = 2). Tissues were diced into 1-mm cubes, immersion fixed overnight in 2.5% glutaraldehyde, followed by postfixation at room temperature for 1.5 h in 1.0% osmium tetroxide in 0.1 M cacodylate buffer, pH 7.3. Tissues were then dehydrated in graded ethanol (70–100%) and embedded in Epon. Survey sections 1.5 µm thick were stained with toluidine blue. Ultrathin sections were cut with a diamond knife on a Sorval MT2B Ultramicrotome, stained with uranyl acetate and lead citrate, and examined under a JEOL 100S (JEOL, Tokyo, Japan) electron microscope.

Lendrum staining
Slides containing thin sections cut from fixed-embedded tissues (control, unoperated, and 24-h castrated ventral prostates) were deparaffinized (2 fis), rehydrated, and then stained according to the modified Lendrum Fraser procedure used for identifying fibrin in tissues (8). This procedure stains fibrin as reddish purple, whereas areas of tissue without fibrin stain greenish/blue.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The TUNEL labeling procedure was used to immunostain thin sections of ventral prostate tissues obtained from control unoperated rats and from rats at different times after castration. TUNEL-positive and -negative cells were counted using a light microscope, and the percent TUNEL-positive cells was calculated for the endothelial, (nonendothelial) stromal, and epithelial cell populations of the tissue. Figure 1Go shows the mean percentage of TUNEL-positive cells for each of these three populations as a function of time after castration. For the endothelial cell population of the prostate, increased TUNEL labeling was detected as early as 12 h after castration, with 2.15% of these cells staining positive, similar to our previous observations (3). In our previous study, however, the increased TUNEL labeling of endothelial cells at 12 h after castration was significantly elevated compared with that in control tissues, whereas in this experiment, the percentage of endothelial cell labeling did not reach a statistically significant difference from the control value until 24 h, when 6.08% of the ventral prostate endothelial cell population were stained by the TUNEL assay (P = 0.0236). The curve for counts of nonendothelial stromal cells labeled by the TUNEL assay was similar to that of the endothelial cells, with an increase detected at 12 h after castration that already reached significance compared with that in the ventral prostates of control unoperated rats (P = 0.0014). Both of these groups returned to control levels by 96 h after castration. In contrast, increased TUNEL labeling of the epithelial cell population was not apparent until 24 h after castration, and this increase did not reach significance (compared with control tissues) until 72 h after castration, when approximately 5% of the epithelial cell population was labeled. Likewise, increased TUNEL labeling of epithelial cells was apparent even at 144 h after castration.



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  		Figure 1. Quantification of TUNEL-labeled cells in the rat ventral prostate after castration. Thin sections of ventral prostate tissues obtained at different times after castration were immunostained using the TUNEL method to identify cells undergoing apoptosis. Under microscopy, all TUNEL-labeled endothelial cells or (nonendothelial) stromal cells were counted on each section and were compared with the entire population of endothelial cells or stromal cells on the same section to derive the percentage of the TUNEL-positive population at each time (top and middle panels). The number of TUNEL-positive epithelial cells was counted in 10 fields and was compared with the total number of epithelial cells present in the fields to obtain the percent TUNEL-positive count for these cells (lower panel). Vertical bars identify the SD at each point. An asterisk below the point identifies that this number is significantly different (P < 0.05) from the value in control (uncastrated) tissues.

 
To verify that our approach of counting TUNEL-labeled endothelial cells based on a direct morphological assessment of cell types was accurate, we performed a dual immunostaining procedure only on sections of tissue obtained at 12 and 24 h after castration in which TUNEL staining was combined with staining using an antibody against CD31, an antigen expressed on endothelial cells or against smooth muscle actin, a marker of smooth muscle cells. As shown in Fig. 2Go, the dual staining procedure employing anti-CD31 confirmed that the TUNEL-labeled cells associated with vascular elements in the tissue were endothelial in nature. In contrast, when the dual staining procedure was performed with an antismooth muscle actin staining to identify smooth muscle cells in the 24-h castrated ventral prostate, there was only one TUNEL-positive cell in all sections analyzed that could be identified as smooth muscle in nature (not shown), and this cell was in a periglandular position. This indicates that apoptosis of smooth muscle cells in the ventral prostate appears to be a rare event after castration, and it certainly suggests that the vascular-associated cells that stained TUNEL positive were not of smooth muscle origin. Likewise, this latter finding indicates that the (nonendothelial) stromal cells that were labeled by the TUNEL technique at early times after castration were nonspecific fibroblasts.



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  		Figure 2. TUNEL-labeled CD31+ endothelial cells on a thin section from a 24-h castrated rat ventral prostate gland. Five-micron sections were stained by TUNEL labeling methods to identify cells undergoing apoptosis and were subsequently immunostained to confirm the identify of endothelial cells using an anti-CD31 antibody (using a fast red substrate). Sections were counterstained with hematoxylin. Arrows identify two prominent TUNEL-labeled nuclei in red-stained CD31+ cells (x400).

 
The TUNEL staining procedure identifies cells with degraded nuclear DNA. To obtain more stringent morphological evidence for early apoptosis of endothelial cells in the regressing rat ventral prostate, we performed a transmission electron microscopic survey of prostate tissues obtained from rats at 36 and 48 h after castration. We were unable to clearly identify frank apoptosis of endothelial cells in the specimens obtained at 36 h postcastration. These specimens, however, did show the presence of erythrocyte congestion of the periglandular capillary bed. The specimens from 48 h postcastration displayed focal early apoptosis of endothelial cells lining the interstitial capillaries immediately surrounding the prostatic glands (Fig. 3Go, B and C). Early apoptosis was identified by a semilunar margination and condensation of chromatin at the periphery of the nucleus, with loss of the normal finely dispersed chromatin pattern (Fig. 3BGo). At this stage, the endothelial cytoplasm was slightly swollen, but with preservation of intercellular tight junctions and other cytoplasmic organelles. Also, at 48 h after castration, some interstitial capillaries were found to be dilated with prominent erythrocyte congestion and platelet aggregation (Fig. 3CGo). In these capillaries, there was widening of the intercellular spaces between adjacent endothelial cells, with loss of adherence of the endothelial cell to the underlying basement membrane. At these sites, some intracapillary cells displayed more advanced apoptosis, with rounded nuclei containing highly condensed nuclear chromatin and inconspicuous cytoplasm with sparse organelles. Although the identity of these cells is uncertain, their juxta-endothelial location and sparse cytoplasm as well as the perturbation of the adjacent endothelial surface suggest that they may represent desquamated apoptotic capillary endothelial cells. These cells lacked the distinguishing cytoplasmic features of circulating monocytes. No endothelial cells with advanced apoptosis were identified in situ. This failure to identify advanced apoptosis in endothelial lining cells probably relates to their tendency to be shed into the intravascular space where they are rapidly cleared.



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  		Figure 3. Electron microscopic analysis for apoptosis of ventral prostate endothelial cells in the castrated rat. A, Periglandular capillary in a control (noncastrated) rat showing normal elongated cigar-shaped endothelial nucleus with thin layer of peripheral chromatin and central zone of finely dispersed chromatin (thin arrow, E). Large thick arrow identifies red blood cells (x3000). B, Early apoptosis of an interstitial capillary endothelial cell at 48 h postcastration (thin arrow, E). The endothelial cell nucleus is rounded, with loss of its usual elongated shape. There is increased condensation and margination of the peripheral chromatin, forming semilunar condensates. The cytoplasm is slightly swollen but otherwise well preserved (x8000). C, A circulating intracapillary cell with more advanced apoptosis abuts the endothelial surface of an interstitial capillary (thin arrow). The nucleus is rounded and almost completely replaced by highly condensed chromatin, with loss of identifiable nuclear membrane. This cell of uncertain origin may represent a desquamated capillary endothelial cell. The adjacent endothelial cells have widened intercellular junctions (large thick arrow). There is severe intracapillary erythrocyte congestion with platelet aggregation (small thick arrows, P; x6000).

 
Finally, we performed a modified Lendrum Fraser staining procedure that identifies and localizes fibrin on sections of ventral prostate from control and castrated rats. In the control sections (Fig. 4AGo), positive staining (as indicated by the reddish purple) was restricted to the vascular surfaces and to the vascular lumens containing red blood cells. In striking contrast, tissues from castrated rats as early as 24 h after castration had diffuse positive staining outside the blood vessels (Fig. 4BGo). This staining was found in a periglandular fashion, suggesting that fibrin leakage might be relatively confined to the regions between the glands and the smooth muscle layer that surrounds the glands of the rat ventral prostate gland.



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  		Figure 4. Lendrum-Fraser staining identifies fibrin exudation outside the capillaries and vessels of the castrated ventral prostate gland. A, Control ventral prostate section (x200) stained with the Lendrum-Fraser technique is completely negative, with green-staining interstitial connective tissue and glandular basement membranes. Red blood cells in the interstitial capillaries normally stain red. B, Lendrum-Fraser staining of prostate at 24 h after castration (x200) shows widespread positivity in the form of purple staining reaction in the periglandular connective tissue and segments of the basement membranes of the glandular epithelium (large arrows). There is also rare staining of a few glandular epithelial cells.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Like other glandular tissues, the rat prostate is composed of a complex admixture of epithelial cells, fibroblasts, smooth muscle cells, and nerve and endothelial cells interacting to form a branching ductal network that secretes material into the rat ejaculate. This tissue is strictly dependent on androgenic steroids for its development, growth, and adult maintenance. The mechanism for this dependence is presently unknown. Previously, we and others have shown that prostate blood flow declines significantly in the early period after castration (within 24 h) (2, 3). This decline in blood flow seems to precede (or concur) with the initiation of a period in which most of the epithelial cells will undergo apoptosis. As graded or partial ischemia is known to be a potent initiator of apoptosis (9, 10, 11), we have proposed that the decreased blood flow after castration might be a causative factor in the loss of the epithelial cell population (3). However, without convincing data showing that the effects of castration on the epithelial cell population are dependent upon this early degeneration of the prostatic vascular system, we still must consider the possibility that these effects (on the epithelium and endothelium of the prostate) are independent of each other.

As demonstrated by this current study, one of the first cellular events after castration (detectable by 12 h) is a significant loss of ventral prostate endothelial cells by apoptosis. This loss is soon followed by a reduction in total prostate blood flow as well as by leaking of serum components (at least fibrin) into nonvascular spaces, as shown by our Lendrum-Fraser staining results, especially in the regions between the glands and the surrounding smooth muscle layer. If this schema is correct, it places (at least a subset) of the ventral prostate endothelial cells as one of the primary targets for androgen action in the rat prostate gland. Certainly this view is supported by another recent report showing that the vascular endothelial cells of the rat ventral prostate gland are the first to demonstrate proliferative activity when a castrated rat is replenished with testosterone (12).

The idea of the prostate vascular endothelial cell as a primary target of androgen action is highly enigmatic. It is known that androgenic steroids act through an intracellular androgen receptor protein (AR). In the rat ventral prostate gland, AR has been found in most epithelial and smooth muscle cells (periductal and perivascular) and in some fibroblast cells; however, AR has never been detected in the endothelial cells of this tissue (13, 14). Therefore, we must presume that the androgen action on the endothelial cells is mediated by some product made by the AR-positive cells in the prostate in response to androgens. This brings up two important issues for further study: 1) what is the factor(s) that mediates prostate endothelial cell survival in response to androgens? and 2) what is the cell type(s) of the prostate that produces this factor(s) in response to androgens?

At this time, one of the more viable candidates for this activity is vascular endothelial cell growth factor. This substance is currently receiving extensive attention because of its proposed role in driving tumor growth processes (15). As well, it has recently been reported that the expression of VEGF-A messenger RNA isoforms is regulated by androgens in the rat prostate gland in a manner that would be consistent with adverse effects on the prostatic endothelium (16). These latter results require reevaluation, especially to confirm that VEGF peptide synthesis is likewise affected by androgens. It is also important to consider that there are many kinds of proangiogenic factors that are believed to be expressed in the rat prostate gland. These other factors include basic fibroblast growth factor (17), transforming growth factor-ß (18), and adrenomedullin (19), and each of these factors is also apparently regulated by androgens in the rat ventral prostate gland. Rather than simply attributing this effect to any single trophic factor it may be equally important to determine how castration affects the overall milieu of these vascular-regulating trophic factors within the prostate.


   Acknowledgments
 
The authors acknowledge the helpful advice of Dr. Gary Miller, Department of Pathology at the University of Colorado Medical Center.


   Footnotes
 
1 This work was supported by funding provided by the T. J. Martell Foundation and the David Koch Foundation. Back

Received September 18, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Colombel M, Buttyan R 1995 Hormonal control of apoptosis: the rat ventral prostate gland as a model system. Methods Cell Biol 46:369–385[Medline]
  2. Lekas E, Johansson M, Widmark A, Berg A, Damber J-E 1997 Decrement of blood flow precedes the involution of the ventral prostate in the rat after castration. Urol Res 25:309–314[CrossRef][Medline]
  3. Shabsigh A, Chang DT, Heitjan DF, Kiss A, Olsson CA, Puchner PJ, Buttyan R 1998 Rapid reduction in blood flow to the rat ventral prostate gland after castration: preliminary evidence that androgens influence prostate size by regulating blood flow to the prostate gland and prostate endothelial cell survival. Prostate 36:201–206[CrossRef][Medline]
  4. Gavereli Y, Sherman Y, Ben-Sasson SA 1992 Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119:493–501[Abstract/Free Full Text]
  5. Sanford ML, Searle JW, Kerr JFR 1984 Successive waves of apoptosis in the rat prostate after repeated withdrawal of testosterone stimulation. Pathology 16:406–410[Medline]
  6. Berges RR, Furuya Y, Remington L, English HF, Jacks T, Isaacs JT 1993 Cell proliferation, DNA repair and p53 function are not required for the programmed death of prostatic glandular cells induced by androgen ablation. Proc Natl Acad Sci USA 90:8910–1914[Abstract/Free Full Text]
  7. English HF, Drago JR, Santen RJ 1985 Cellular response to androgen depletion and repletion in the rat prostate: autoradiography and morphometric analysis. Prostate 7:41–51[Medline]
  8. Lendrum AC, Fraser DS, Slidders W, Menderson R 1962 Studies on the character and staining of fibrin. J Clin Pathol 14:401–413
  9. Schumer M, Colombel MC, Sawczuk IS, Gobé G, Connor J, O’Toole KM, Olsson CA, Wise GJ, Buttyan R 1992 Morphological, biochemical and molecular evidence of apoptosis during the reperfusion phase following brief periods of renal ischemia. Am J Pathol 140:831–838[Abstract]
  10. Gobé G, Axelson RA, Searle JW 1990 Cellular events in experimental unilateral ischemic renal atrophy and in regeneration after contralateral nephrectomy. Lab Invest 63:770–779[Medline]
  11. MacLellan WR, Schneider MD 1997 Death by design. Programmed cell death in cardiovascular biology and disease. Circ Res 81:137–144[Abstract/Free Full Text]
  12. Franck-Lissbrant I, Häggström S, Damber J-E, Bergh A 1998 Testosterone stimulates angiogenesis and vascular regrowth in the ventral prostate in castrated rats. Endocrinology 139:451–456[Abstract/Free Full Text]
  13. Prins GS, Birch L, Greene GL 1991 Androgen receptor localization in different cell types of the adult rat prostate. Endocrinology 129:3187–3199[Abstract]
  14. Prins GS, Birch L 1993 Immunocytochemical analysis of androgen receptor along the ducts of the separate rat prostate lobes after androgen withdrawal and replacement. Endocrinology 132:169–178[Abstract]
  15. Senger DR, Brown LF, Claffey KP, Dvorak HF 1994 Vascular permeability factor, tumor angiogenesis and stroma generation. Invasion Metastasis 14:385–394[Medline]
  16. Häggström S, Wikström P, Bergh A, Damber J-E 1998 Expression of vascular endothelial growth factor and its receptors in the rat ventral prostate and Dunning R3327 PAP adenocarcinoma before and after castration. Prostate 36:71–79[CrossRef][Medline]
  17. Bacher M, Rausch U, Goebel HW, Polzar B, Mannherz HG, Aumuller G 1993 Stromal and epithelial cells from rat ventral prostate during androgen deprivation and estrogen treatment–regulation of transcription. Exp Clin Endocrinol 101:78–86[Medline]
  18. Kyprianou N, Isaacs JT 1989 Expression of transforming growth factor-ß in the rat ventral prostate during castration-induced programmed cell death. Mol Endocrinol 3:1515–1522[Abstract]
  19. Wang Z, Tufts R, Haleem R, Cai X 1997 Genes regulated by androgen in the rat ventral prostate. Proc Natl Acad Sci USA 94:12999–13004[Abstract/Free Full Text]



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