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Altered Levels of Angiopoietin 1 and Tie 2 Are Associated with Androgen-Regulated Vascular Regression and Growth in the Ventral Prostate in Adult Mice and Rats

Department of Medical Bioscience, Pathology (A.J., P.W., A.B.), and Department of Surgical and Perioperative Sciences, Urology and Andrology (S.H.R.), Umeå University, 901 85 Umeå, Sweden

Address all correspondence and requests for reprints to: Anders Bergh, Department of Medical Bioscience, Pathology, Umeå University, 901 85 Umeå, Sweden. E-mail: anders.bergh{at}medbio.umu.se.

The involution of the rat ventral prostate gland after castration could be caused by primary changes in the vasculature. To explore the mechanisms, we studied the effects of castration and testosterone treatment on the vasculature in the ventral prostate in adult rats and mice. Androgen receptor expression, vascular morphology, and the expression of angiopoietin (ang) 1 and 2 and their receptor tie 2 were examined 1, 3, and 7 d after castration and after testosterone treatment of castrated animals using stereological methods, immunohistochemistry, laser capture microdissection, and Western blotting. One day after castration, the percentage of blood vessels covered with smooth muscle actin, endothelial cell proliferation, and vascular volume had decreased, whereas endothelial cell apoptosis had increased. Simultaneously, ang 1 and tie 2 protein levels decreased. Nuclear expression of androgen receptor was observed not only in glandular and stroma smooth muscle cells but also in the mural cells of prostate arteries and veins and was markedly down-regulated already 1 d after castration. Testosterone administration of castrated mice and rats reversed all the observed effects. At the mRNA level, tie 2 was exclusively, but ang 1 predominantly, expressed in the stroma, compared with the epithelial compartment. Local delivery of soluble tie 2 during testosterone-stimulated growth, inhibited vascular maturation and increased vascular volume and leukocyte infiltration compared with controls. We conclude that androgens may regulate the prostate vasculature by direct effects on mural vascular cells and by influencing the secretion of the angiopoietins, in above all, the stroma cells.

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