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Endocrinology Vol. 139, No. 2 451-456
Copyright © 1998 by The Endocrine Society

ARTICLES

Testosterone Stimulates Angiogenesis and Vascular Regrowth in the Ventral Prostate in Castrated Adult Rats1

Ingela Franck-Lissbrant, Stina Häggström, Jan-Erik Damber and Anders Bergh

Departments of Pathology (I.F.-L., A.B.) and Urology and Andrology (S.H., J.-E.D.), Umeå University, 901 87 Umeå, Sweden

Address all correspondence and requests for reprints to: Anders Bergh, Department of Pathology, Umeå University, 901 87 Umeå, Sweden. E-mail: anders.bergh{at}pathol.umu.se


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The castration-induced regression and testosterone stimulated regrowth of the vasculature in the rat ventral prostate lobe were studied using stereological techniques. Seven days after castration, the endothelial cell proliferation rate (bromodeoxyuridine labeling index); the total weights of blood vessel walls, blood vessel lumina, endothelial cells, glandular epithelial cells; and total organ weight were all decreased. Within 2 days after sc treatment with testosterone, the total weights of blood vessel walls, endothelial cells, and vascular lumina, as well as the endothelial cell proliferation rate, were all normalized. In contrast to the rapid response of the vasculature, the total weight of glandular epithelium and total organ weight were not normalized during the 4 days of testosterone treatment. Growth of the vasculature apparently precedes growth of the glandular epithelium. The testosterone- dependent factors stimulating the vasculature are unknown, but factors derived from epithelial cells, mast cells (which accumulate in the prostate during the first day of testosterone treatment), and tissue macrophages could all be involved. Castration-induced regression and testosterone-stimulated regrowth of the prostatic vasculature can be used as an experimental model to study factors regulating angiogenesis and organ growth in the prostate.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
VASCULAR density and vascular invasion are related to the risk of extraprostatic growth (1), metastasis (2, 3), disease progression (4), and cancer-specific survival (5) in prostate cancer patients. In addition, the growth of a human prostate cancer cell line (PC3) in nude mice is remarkably inhibited after treatment with the angiogenesis inhibitor angiostatin (6). The castration-induced involution of the rat ventral prostate is preceded by a marked decrease in organ blood flow (7). These recent observations suggest that the vasculature could play a more central role in the regulation of the normal prostate and prostate tumors than earlier recognized. The factors controlling blood flow, endothelial cell proliferation, and other aspects of angiogenesis in the normal prostate and in prostate cancers are however largely unknown.

Previous studies have suggested that castration reduces endothelial cell numbers and the endothelial cell proliferation rate in the adult rat ventral prostate, and that they are normalized by testosterone treatment (8). Similarly, castration decreases and testosterone treatment rapidly normalizes blood flow to the adult rat ventral prostate (7). These studies indicate that the vasculature could be regulated, directly or indirectly, by androgens. If this is the case, castration-induced involution and testosterone-stimulated regrowth could be used to study factors regulating angiogenesis, vascular growth, and local blood flow in the normal prostate, and to examine the role of vascular factors in prostate physiology and pathology. The aim of this study therefore was to examine, in detail, how the prostate vasculature responds to castration and testosterone treatment. An understanding of this may expand our knowledge of factors regulating growth in the normal prostate and in prostate tumors.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals and treatments
Adult male Sprague-Dawley rats (weight 285–430 g) were anesthetized with pentobarbital (50 mg/kg) (Möllegaard A/S, Li Skensved, Denmark), and castration was performed via the scrotal route. Intact animals served as controls. After 7 days, some of the castrated animals received a sc injection of long-acting testosterone (Organon, OSS, The Netherlands) esters (5 mg/kg; Sustanon, kindly donated by Organon, The Netherlands) every second day. This treatment results in sustained supraphysiological levels of testosterone in serum (9). The following groups of rats (intact, 7-day castrated, 8-day castrated + testosterone-treated, 9-day castrated + testosterone-treated, 10-day castrated + testosterone-treated, and 11-day castrated + testosterone-treated) were used in the experiments. On the day of experiment, the animals were injected with bromodeoxyuridine (BrdU, 50 mg/kg, ip; Sigma, St. Louis, MO), a thymidine analog that is incorporated into DNA in the S-phase of the cell cycle. One hour later the rats were anesthetized with pentobarbital and perfusion fixed via a cannula inserted in the left ventricle of the heart (pressure 1.3 m H2O) using Bouins solution. After perfusion for 15 min, the prostate lobes were carefully dissected out and weighed. The ventral prostate was subsequently fixed by immersion for 2 h in the same fixative, dehydrated, and embedded in paraffin. The design of this study was approved by the local animal ethical committee in Umeå, Sweden.

Stereology
Four-micrometer thick sections of the whole ventral prostate lobe were stained with hematoxylin and eosin, with toluidine blue (to stain mast cells), and by immunohistochemistry (as described below), and examined in a light microscope equipped with a square lattice (121 points) in the eyepiece. Using point counting morphometry as described by Weibel (10), i.e. counting the number of grid intersections (hits) falling on the measured tissue compartment and reference space, the volume density (percentage of tissue volume occupied by the defined tissue compartment) of various parts of the prostate was determined. In randomly chosen areas, the following measurements were performed. First, the volume density of stroma, glandular lumen, and glandular epithelium was obtained by counting the number of hits falling on each of these tissue compartments, respectively, at x100 magnification. Second, the volume density of blood vessel lumina, endothelial cells, blood vessel walls (endothelium + pericyte + muscular coat), mast cells, and immunostained macrophages in the stroma was measured at x400 magnification by counting hits falling on the respective tissue component and on stroma.

The total weight (= volume) of the different stroma components per ventral prostate was determined by total lobe weight x volume density of stroma x volume density of the respective stroma component. In these calculations, we assume that the specific gravity of prostate tissue is 1.0 (8), and that changes in tissue volume during fixation and tissue processing influence all groups in the same way.

Immunohistochemistry
Bromodeoxyuridine. Four-micrometer thick paraffin sections were immunostained with a monoclonal antibody against BrdU (Dako, Älvsjö, Sweden) using biotinylated goat antimouse IgG and a peroxidase-labeled ABC reagent (Vector Labs., Burlingame, CA). The percentage of BrdU-labeled epithelial and endothelial cells were measured in each ventral prostate; 800-1000 cells of each type were examined in each organ.

Macrophages. Four-micrometer thick sections were deparaffinated, rehydrated, heated in a microwave oven (600 W for 2 x 5 min in citrate buffer 0.01 M, pH 6) (11), and immunostained with a monoclonal antibody against macrophages (ED-1; Serotec Ltd., Oxford, UK). The ED-1 antibody recognizes tissue macrophages and monocytes and can be used on paraffin- embedded tissue (12).

Statistical analyses
Values are presented as means ± SEM of 5–10 observations. Groups were compared using the Mann-Whitney U test. A P value <0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Seven days after castration, major reductions in total epithelial weight (-85%), total stromal weight (-50%, data not shown), and total ventral prostate lobe weight (-81%), as well as the total weights of blood vessel lumina (-56%), blood vessel walls (-47%), and endothelial cells (-56%) were seen. Furthermore, the BrdU-labeling indices in epithelial (-86%) and endothelial cells (-91%) were also reduced compared with those in intact animals ( Figs. 1–3GoGoGo).



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  		Figure 1. Histogram showing total weight (g) of ventral prostate lobe (open bars) and glandular epithelium (solid bars) in ventral prostate of intact; 7-day castrated; and 8-, 9-, 10-, and 11-day castrated rats substituted with testosterone from day 7 (t). Values are means and bars indicate SEM; n = 5–10. a, Significantly different than in intact animals, P < 0.05; b, significantly different than in 7-day castrated rats, P < 0.05.

 


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  		Figure 2. Histogram showing total weight (mg) of vessel lumina (open bars), vascular walls (solid bars), and endothelial cells (hatched bars) in ventral prostate of intact; 7-day castrated; and 8-, 9-, 10-, and 11-day castrated rats substituted with testosterone from day 7 (t). Values are means and bars indicate SEM, n = 5–10. a, Significantly different than in intact animals, P < 0.05; b, significantly different than in 7-day castrated rats, P < 0.05.

 


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  		Figure 3. Histogram showing endothelial (open bars) and epithelial cell (solid bars) BrdU-labeling index (%) in ventral prostate of intact; 7-day castrated, and 8-, 9-, 10-, and 11-day castrated rats substituted with testosterone from day 7 (t). Values are means and bars indicate SEM, n = 5–10. a, Significantly different than in intact animals, P < 0.05; b, significantly different than in 7-day castrated rats, P < 0.05.

 
After testosterone treatment, the ventral prostate, total epithelial cell, and stromal weights (not shown) gradually increased. They did not, however, reach the levels in intact animals during the study period (Fig. 1Go). In contrast, the total weights of endothelial cells, blood vessel walls, and vascular lumina were all normalized after only 1–2 days of testosterone treatment (Fig. 2Go). Particularly rapid was the testosterone-stimulated increase in the total weight of vascular lumina. A 3-fold increase was observed after only 1 day. The endothelial cell BrdU-labeling index was slightly increased after 1 day and normalized after 2 days (Figs. 3Go and 4Go).



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  		Figure 4. Sections from ventral prostate in intact (a), 7-day castrated (b), and 9-day castrated + testosterone-treated (c) rats immunostained to demonstrate BrdU-labeled cells. Magnification, x400. In intact rats, some epithelial (arrows) and a few endothelial cells (arrowhead) are labeled. Very few cells are labeled 7 days after castration, but after 2 days of testosterone treatment numerous epithelial (arrows) and endothelial cells (arrowheads) are labeled. Mast cells (*) are often observed close to blood vessels (v).

 
In intact animals, some mast cells were observed in the prostate stroma, often close to blood vessels. Seven days after castration, the volume density and the total weight of mast cells per prostate were increased. Testosterone treatment resulted in a transient increase in mast cell weight at day 8, thereafter it gradually decreased toward the values in intact rats (Fig. 5Go and Table 1Go). At days 8–11, mast cells were often observed close to BrdU-labeled endothelial cells (Fig. 4Go).



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  		Figure 5. Sections from ventral prostate in intact (a), 7-day castrated (b), and 8-day castrated + testosterone-treated (c) rats stained with toluidine blue to demonstrate mast cells. Magnification, x400. In intact rats, some mast cells (arrows) are observed in stroma often close to blood vessels (v). Seven days after castration, numerous mast cells are observed in stroma (b), and their numbers are increased further after 1 day of testosterone treatment (c).

 

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  		Table 1. Volume densities (%) and total weights (mg) of mast cells and ED-1-expressing macrophages in ventral prostate of intact, 7-day castrated, and castrated testosterone-treated rats at different times after treatment

 
Some ED-1-immunostained macrophages are observed in the stroma and epithelium of the ventral prostate in intact rats. Seven days after castration, the number of ED-1-stained cells was markedly increased in the epithelium (not quantified) and in the stroma (Fig. 6Go and Table 1Go). Treatment with testosterone rapidly decreased the number of macrophages in the epithelium (Fig. 6Go) and gradually decreased the volume density of macrophages in the stroma (Fig. 6Go and Table 1Go).



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  		Figure 6. Sections from ventral prostate in intact (a), 7-day castrated (b), and 9-day castrated + testosterone-treated (c) rats immunostained to demonstrate ED-1-expressing macrophages. Magnification, x200. In intact rats, some macrophages are observed in epithelium and some in stroma (a, arrows). Seven days after castration, numerous macrophages are present in epithelium (arrows) and some in stroma (b), but after 2 days of testosterone treatment, the number of ED-1 macrophages is decreased both in epithelium and in stroma.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study shows, in line with and extending the observations of English et al. (8), that castration induces a marked involution of the vasculature in the adult rat ventral prostate. Androgen receptors are observed in epithelial and stromal cells but not in blood vessels in the ventral prostate (7), suggesting that the vascular effect is secondary to changes in other prostatic cells. The magnitude of the castration-induced decrease in vascular weights (approximately -50%) was not as large as that in epithelial cell and organ weights (approximately -80%). Lekås et al. (7) recently showed, however, that total blood flow per ventral prostate lobe was reduced by 92% 7 days after castration. The magnitude of this decrease is similar to that in epithelial cell numbers [reduced by 94% in English et al., (8)] and weight (reduced by 86% in this study), indicating a relationship between the epithelium and blood flow.

Endothelial cell proliferation and regrowth of the vasculature are stimulated by testosterone in the regressed ventral prostate. The effect is rapid and occurs quicker than that of the glandular epithelium. Vascular weights are normalized after 2 days, but epithelial cell, stromal, and organ weights are not normalized until several days later (8). Endothelial cell proliferation starts earlier than the proliferation in the epithelium. In addition, testosterone apparently induces a rapid vasodilatation, because the total weight of blood vessel lumina (present study) and blood flow (7) are normalized after only 1 day of testosterone substitution. The rapid normalization of blood flow and vascular tissue weights after 1–2 days, respectively, can probably not be explained only by proliferation of vascular cells (peaking after 2–4 days). Our data therefore suggests that testosterone treatment induces, with different kinetics, vasodilators, factors increasing the size of vascular wall cells, and endothelial cell mitogens. The increased metabolic demand of the testosterone-stimulated prostate is apparently first met by vasodilatation of existing blood vessels and increased blood flow, and later by proliferation and growth of vascular cells. The observation that growth of the glandular epithelium is preceded by growth in the vasculature suggests that vascular growth could be a prerequisite for organ growth. It remains to be shown whether growth of a prostate tumor is preceded by growth of its vasculature. The observation of an increased vascular density in relation to prostatic intraepithelial neoplasia lesions do, however, suggest that this may be the case (13).

In line with English et al. (8), we observed that 1–2% of the endothelial cells in the intact ventral prostate are proliferating. This is a rather high figure compared with other normal tissues in which the labeling indices ranges from 0.01–1% (14). The relatively high endothelial cell proliferation rate may be related to the observation that the potent endothelial cell mitogens vascular endothelial cell growth factor (VEGF) (15), VEGF-B (16), and VEGF-C (17, 18) are all produced locally in the prostate. Endothelial cell proliferation is probably balanced by endothelial cell death. Previous investigators have, however, not detected apoptosis in prostatic blood vessels in normal or castrated animals (19). However, castration-induced death of prostatic endothelial cells is, although difficult to detect, not unlikely, because tissue involution generally is accompanied by endothelial cell death (20, 21).

The present observations suggest that testosterone treatment induces the synthesis of an angiogenic factor (endothelial cell mitogen), or that testosterone up-regulates the expression of endothelial receptors for angiogenic factors, or that testosterone decreases the synthesis of an angiogenesis inhibitor. In line with the first suggestion, we recently showed that castration decreases and testosterone treatment increases VEGF messenger RNA expression in the ventral prostate (S. Häggström, our unpublished observations). In the prostate, VEGF is expressed only in glandular epithelial cells (15) (our unpublished observations). These observations may suggest that the angiogenic effect of testosterone could be mediated via VEGF synthesis in the epithelial cells. Another substance that could be involved is epidermal growth factor (22), which is decreased by castration and stimulated by testosterone (23). Several other factors that stimulate angiogenesis in other tissues (22), such as basic fibroblast growth factor (b-FGF), transforming growth factor-ß1 (TGF-ß1), and hepatocyte growth factor, are produced in the prostate but they are all up-regulated by castration and down-regulated by testosterone treatment (23), suggesting that they are not involved in the testosterone-dependent changes observed in the present study.

Apart from the glandular epithelial cells, other cell types could also be involved in the vascular control of the prostate. Numerous mast cells are observed in the stroma of the rat ventral prostate, and they are often observed close to blood vessels (24). In other tissues, mast cells are involved in angiogenesis (25) and in the control of local blood flow and inflammation (26). In this study, we observe a castration-induced increase and a transient but more pronounced increase in mast cells in the ventral prostate 1 day after testosterone treatment. Mast cells are often observed in close relation to proliferating endothelial cells. It is therefore not unlikely that they could be involved in the initial phase of the testosterone-induced vascular response in the ventral prostate. The mast cell products involved and the mechanisms attracting mast cell to the prostate are at present unknown, but interestingly, VEGF, TGF-ß, and b-FGF (TGF-ß and b-FGF are increased by castration, see above) are all chemotactic for mast cells (27, 28).

Tissue macrophages play an important role for angiogenesis in wound healing and in tumors (29, 30), and inhibition of macrophage influx and tumor necrosis factor synthesis inhibit angiogenesis and growth in rat prostatic tumors (31). Castration increases the number of macrophages in the prostate, but their numbers return to intact values after testosterone treatment. This may suggest that this cell type is a less likely source of the testosterone-induced vascular stimulators than epithelial and/or mast cells. However, because numerous macrophages are present in the prostate at the start of testosterone-induced vascular regrowth, it cannot be excluded that they could play a role in this process.

In summary, the present study suggests that castration-induced involution and testosterone-stimulated regrowth of the vasculature can be used as a model to study the kinetics and origin of the molecular factors that regulate vascular growth, angiogenesis, and local blood flow in the prostate. It is not unlikely that similar factors could be of importance for the growth of androgen-dependent prostate tumors.


   Acknowledgments
 
Ms. Pernilla Anderson, Mrs. Elisabeth Dahlberg, Mrs. Birgitta Ekblom, Mrs. Sigrid Kilter, and Mrs. Ulla Hedlund significantly contributed to this paper by their skillful technical assistance.


   Footnotes
 
1 This work was supported by grants from the Swedish Cancer Society (project 1760), the University hospital in Umeå, the Maud and Birger Gustavsson Foundation, and the Lions Research Foundation University of Umeå. Back

Received June 23, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Bostwick D.G, Wheeler TM, Blute M, Barrett DM, MacLennan GT, Sebo TJ, Scardino PT, Humphrey PA, Hudson MA, Fradet Y, Miller GJ, Crawford ED, Blumenstein BA, Mahran HE, Miles BJ 1996 Optimized microvessel density analysis improves prediction of cancer stage from prostate needle biopsies. Urology 48:47–57[CrossRef][Medline]
  2. Wakui S, Furusato M, Ihto T, Sasaki H, Akiyama A, Kinoshita I, Asano K, Tokuda T, Aizawa S, Ushigome S 1992 Tumor angiogenesis in prostatic carcinoma with and without metastasis: a morphometric study. J Pathol 168:257–262[CrossRef][Medline]
  3. Weidner N, Carroll PR, Flax J, Blumenfeld W, Folkman J 1993 Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 143:401–409[Abstract]
  4. McNeal JE, Yemoto CEM 1996 Significance of demonstrable vascular space invasion for the progression of prostatic adenocarcinoma. Am J Surg Pathol 20:1351–1360[CrossRef][Medline]
  5. Franck-Lissbrant I, Stattin P, Damber J-E, Bergh A 1997 Vascular density is a predictor of cancer specific survival in prostatic carcinoma. Prostate 33:38–45[CrossRef][Medline]
  6. O‘Reilly M, Holmgren L, Chen C, Folkman J 1996 Angiostatin induces and sustains dormancy of human primary tumors in mice. Nature Medicine, 2:689–692[CrossRef][Medline]
  7. Lekås E, Johansson M, Widmark A, Bergh 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]
  8. English HF, Drago JR, Santen RJ 1985 Cellular response to androgen depletion and repletion in the rat ventral prostate: autoradiographic and morphometrical analysis. Prostate 7:41–51[Medline]
  9. Sharpe RM, Maddocks S 1989 Evaluation of relative importance of endocrine and paracrine factors in the control of levels of inhibin in testicular interstitial fluid. Int J Androl 12:295–306[Medline]
  10. Weibel, ER 1979 Stereological methods. Vol 1: Practical methods for biological morphometry. Academic Press, London, pp 1–415
  11. Taylor CR, Shi SR, Chaiwun B, Young L, Imam SA, Cote RJ 1994 Strategies for improving the immunohistochemical staining of various intranuclear prognostic markers in formalin-paraffin sections: androgen receptor, estrogen receptor, progesterone receptor p53 protein, proliferating nuclear cell antigen, and Ki-67 antigen revealed by antigen retrieval techniques. Hum Pathol 25:263–270[CrossRef][Medline]
  12. Dijkstra CD, Döpp JP, Kraal G 1985 The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in the rat recognized by mononuclear antibodies ED1, ED2, ED3. Immunology 54:589–599[Medline]
  13. Montironi R, Magi Galluzzi C, Diamanti L, Taborro R, Scapelli M, Pisani E 1993 Prostatic intra-epithelial neoplasia. Qualitative and quantitative analyses of the blood capillary architecture on thin tissue sections. Pathol Res Pract 189:542–548[Medline]
  14. Denekamp J 1993 Angiogenesis, neovascular proliferation and vascular pathophysiology as targets for cancer therapy. Br J Radiol 66:181–196[Abstract]
  15. Brown LF, Yeo K-T, Berse B, Morgentaler A, Dvorak HF, Rosen S 1995 Vascular permeability factor (vascular endothelial growth factor) is strongly expressed in the normal male genital tract and is present in substantial quantities in semen. J Urol 154:576–579[CrossRef][Medline]
  16. Olofsson B, Pajusola K, Kaipainen A, Euler G, Joukov V, Saksela O, Orpana, A, Pettersson RF, Alitalo K, Eriksson U 1996 Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc Natl Acad Sci USA 93:2576–2581[Abstract/Free Full Text]
  17. Joukov V, Pajusola, K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K 1996 A novel vascular endothelial growth factor, VEGF-C, is a ligand for the flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J 15:290–298[Medline]
  18. Lee J, Gray A, Yuan J, Luoh S-M, Avraham H, Wood WI 1996 Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4. Proc Natl Acad Sci USA 93:1988–1992[Abstract/Free Full Text]
  19. English HF, Kyprianou N, Isaacs JT 1996 Relationship between DNA fragmentation and apoptosis in the programmed cell death in the rat prostate following castration. Prostate 15:233–250
  20. Walker NI, Bennet RE, Kerr JFR 1989 Cell death by apoptosis during involution of the lactating breast in mice and rats. Am J Anat 185:19–32[CrossRef][Medline]
  21. Modlich U, Kaup F-J, Augustin HG 1996 Cyclic angiogenesis and blood vessel regression in the ovary: blood vessel regression during luteolysis involves endothelial detachment and vessel occlusion. Lab Invest 74:71–780
  22. Bouck N, Stellmach V, Hsu SC 1996 How tumors become angiogenic. Adv Cancer Res 69:135–174[Medline]
  23. Nihshi N, Oya H, Matsumoto K, Nakamura T, Miyanaka H, Wada F 1996 Changes in gene expression of growth factors and their receptors during castration-induced involution and androgen-induced regrowth of rat prostates. Prostate 28:139–152[CrossRef][Medline]
  24. Hammel I, Roizman P, Massas R, Abramovici A 1990 Ontogeny of mast cells in the ventral prostate of the rat. Int Arch Allergy Appl Immunol 93:212–215[Medline]
  25. Meiniger CJ, Zetter BR 1992 Mast cells and angiogenesis. Cancer Biol 3:73–79
  26. Raud J 1989 Intravital microscopic studies on acute mast cell-dependent inflammation. Acta Physiol Scand 135[Suppl 587]:1–58
  27. Gruber BL, Marchese MJ, Kew R 1994 Transforming growth factor-ß1 mediates chemotaxis of mast cells. J Immunol 152:5860–5865[Abstract]
  28. Gruber BL, Marchese MJ, Kew R 1995 Angiogenic factors stimulate mast-cell migration. Blood 7:2488–2493
  29. Hildenbrand R, Dilger I, Hörlin A, Stutte HJ 1995 Urokinase and macrophages in tumour angiogenesis. Br J Cancer 72:818–823[Medline]
  30. Polverini PJ 1990 Macrophage induced angiogenesis: a review. Cytokines 1:54–73
  31. Vukanovic J, Isaacs JT 1995 Linomide inhibits angiogenesis, metastasis, macrophage infiltration within rat prostatic cancers. Cancer Res 55:1499–1504[Abstract/Free Full Text]



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 Endocr. Rev.Home page
C. A. Heinlein and C. Chang
Androgen Receptor in Prostate Cancer
Endocr. Rev., April 1, 2004; 25(2): 276 - 308.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
P. V. Nantermet, J. Xu, Y. Yu, P. Hodor, D. Holder, S. Adamski, M. A. Gentile, D. B. Kimmel, S.-i. Harada, D. Gerhold, et al.
Identification of Genetic Pathways Activated by the Androgen Receptor during the Induction of Proliferation in the Ventral Prostate Gland
J. Biol. Chem., January 9, 2004; 279(2): 1310 - 1322.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
D. Fukumura, A. Ushiyama, D. G. Duda, L. Xu, J. Tam, V. Krishna, K. Chatterjee, I. Garkavtsev, and R. K. Jain
Paracrine Regulation of Angiogenesis and Adipocyte Differentiation During In Vivo Adipogenesis
Circ. Res., October 31, 2003; 93 (9): e88 - e97.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
H. E. Turner, A. L. Harris, S. Melmed, and J. A. H. Wass
Angiogenesis in Endocrine Tumors
Endocr. Rev., October 1, 2003; 24(5): 600 - 632.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
I. Franck Lissbrant, E. Lissbrant, A. Persson, J.-E. Damber, and A. Bergh
Endothelial Cell Proliferation in Male Reproductive Organs of Adult Rat Is High and Regulated by Testicular Factors
Biol Reprod, April 1, 2003; 68(4): 1107 - 1111.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
J. M. Hastings, D. R. Licence, G. J. Burton, D. S. Charnock-Jones, and S. K. Smith
Soluble Vascular Endothelial Growth Factor Receptor 1 Inhibits Edema and Epithelial Proliferation Induced by 17{beta}-Estradiol in the Mouse Uterus
Endocrinology, January 1, 2003; 144(1): 326 - 334.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
P. Fournier, S. Boissier, S. Filleur, J. Guglielmi, F. Cabon, M. Colombel, and P. Clezardin
Bisphosphonates Inhibit Angiogenesis in Vitro and Testosterone-stimulated Vascular Regrowth in the Ventral Prostate in Castrated Rats
Cancer Res., November 15, 2002; 62(22): 6538 - 6544.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
W. D. Fox, B. Higgins, K. M. Maiese, M. Drobnjak, C. Cordon-Cardo, H. I. Scher, and D. B. Agus
Antibody to Vascular Endothelial Growth Factor Slows Growth of an Androgen-independent Xenograft Model of Prostate Cancer
Clin. Cancer Res., October 1, 2002; 8(10): 3226 - 3231.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
M. A. Rupnick, D. Panigrahy, C.-Y. Zhang, S. M. Dallabrida, B. B. Lowell, R. Langer, and M. J. Folkman
From the Cover: Adipose tissue mass can be regulated through the vasculature
PNAS, August 6, 2002; 99(16): 10730 - 10735.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
M. Mattioli, B. Barboni, M. Turriani, G. Galeati, A. Zannoni, G. Castellani, P. Berardinelli, and P. A. Scapolo
Follicle Activation Involves Vascular Endothelial Growth Factor Production and Increased Blood Vessel Extension
Biol Reprod, October 1, 2001; 65(4): 1014 - 1019.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
G. G. Geary, D. N. Krause, and S. P. Duckles
Gonadal hormones affect diameter of male rat cerebral arteries through endothelium-dependent mechanisms
Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H610 - H618.
[Abstract] [Full Text] [PDF]

Home page
 J. Histochem. Cytochem.Home page
G. Pelletier, V. Luu–The, B. Têtu, and F. Labrie
Immunocytochemical Localization of Type 5 17ß-Hydroxysteroid Dehydrogenase in Human Reproductive Tissues
J. Histochem. Cytochem., June 1, 1999; 47(6): 731 - 738.
[Abstract] [Full Text]

Home page
 EndocrinologyHome page
A. Shabisgh, N. Tanji, V. D’Agati, M. Burchardt, M. Rubin, E. T. Goluboff, D. Heitjan, A. Kiss, and R. Buttyan
Early Effects of Castration on the Vascular System of the Rat Ventral Prostate Gland
Endocrinology, April 1, 1999; 140(4): 1920 - 1926.
[Abstract] [Full Text]

Home page
 EndocrinologyHome page
M. El-Alfy, V. Luu-The, X.-F. Huang, L. Berger, F. Labrie, and G. Pelletier
Localization of Type 5 17{beta}-Hydroxysteroid Dehydrogenase, 3{beta}-Hydroxysteroid Dehydrogenase, and Androgen Receptor in the Human Prostate by in Situ Hybridization and Immunocytochemistry
Endocrinology, March 1, 1999; 140(3): 1481 - 1491.
[Abstract] [Full Text]

Home page
 EndocrinologyHome page
A. C. Levine, X.-H. Liu, P. D. Greenberg, M. Eliashvili, J. D. Schiff, S. A. Aaronson, J. F. Holland, and A. Kirschenbaum
Androgens Induce the Expression of Vascular Endothelial Growth Factor in Human Fetal Prostatic Fibroblasts
Endocrinology, November 1, 1998; 139(11): 4672 - 4678.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. Zaina and S. Squire
The Soluble Type 2 Insulin-like Growth Factor (IGF-II) Receptor Reduces Organ Size by IGF-II-mediated and IGF-II-independent Mechanisms
J. Biol. Chem., October 30, 1998; 273(44): 28610 - 28616.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
J. Folkman
Editorial: Is Tissue Mass Regulated by Vascular Endothelial Cells? Prostate as the First Evidence
Endocrinology, February 1, 1998; 139(2): 441 - 442.
[Full Text] [PDF]

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