Prostatic enlargement due to benign prostatic hyperplasia (BPH) and/or prostate cancer are ubiquitous in aging men. While prostate cancer represents the sixth leading cause for cancer-related death worldwide, BPH is known to result in urinary retention and recurrent infections which adversely influences the quality of life among older men. Although inhibitors of the cGMP-hydrolyzing enzyme phospodiesterase 5 (PDE5) are now regularly used for the treatment of BPH, detailed information about their cellular localization and function within the prostate is missing. In prostate tissue of mouse, rat and man, PDE5 was shown to be highly expressed in interstitial and vascular smooth muscle cells (SMCs) but not in epithelial cells of the gland. The newly established CLARITY approach helped to improve our understanding of the prostatic architecture on a three-dimensional level and allowed highly precise reconstructions of the arrangement of PDE5-expressing SMCs. Moreover, this method demonstrated that the interstitial periglandular SMCs in rat prostate are arranged tighter around the glands than in the human prostate. Spontaneous contractions of these SMCs were visualized by the use of time lapse-imaging in both, rodents and men. Addition of the PDE5 inhibitor sildenafil resulted in a significant reduction of the crontractile frequency in both tissues. In rat prostate, spontaneous contractility was only observed in terminal prostatic glands but not in proximal ducts.The regulatory role of sex hormones on the cGMP pathway within prostatic SMCs was another important aspect of this study. In rat, androgen deprivation was induced via castration which increased the expression of prostatic cGMP pathway components considerably. Using estrogen-deficient aromatase knockout (ArKO) and -overexpressing (AROM+) mice, we found only glandular but not vascular smooth muscle cells affected by changes of hormone levels. These findings were consistent even in the human prostate by culturing of isolated prostatic interstitial cells as mRNA expression of cGMP pathway components increased with decreased concentrations of testosterone pretreatment. Data, showing relevant PDE5 effects and their androgen-dependent regulation might be helpful to clarify whether PDE5 inhibitors as new therapeutics aspects for BPH are only effective in case of reduced testosterone levels.
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