Benign prostatic hyperplasia (BPH) is characterized by tissue overgrowth and stromal reorganization primarily due to cellular proliferation and fibroblast-to-myofibroblast transdifferentiation. Given the recently reported beneficial effects of PDE5 inhibitors on lower urinary tract symptoms secondary to BPH this study aimed to investigate the influence of PDE5 inhibition on the prostate at a cellular level. We investigated the expression of PDE5 in the human prostate and demonstrated that PDE5 was mainly present in the stromal compartment of the gland but absent from epithelium.
The effect of PDE5 inhibition on the prostate was thought to be mainly caused by relaxation of smooth muscle lowering urethral pressure and thus affecting the dynamic component of the disease. However, the influence of PDE5 inhibition on proliferation and stromal reorganization (i.e. myofibroblast/fibroblast ratio) has not been investigated in detail.
To evaluate the potential of PDE5 inhibitors like Tadalafil for prevention and treatment of BPH we analyzed the role of the NO/cGMP/PDE5 pathway for cellular proliferation and transforming growth factor β 1 (TGFβ1)-induced fibroblast-to-myofibroblast transdifferentiation in primary prostate stromal cells (PrSC). Inhibition of PDE5 by Tadalafil reduced proliferation of PrSCs and to a lesser extent of primary prostate basal epithelial cells. Attenuated proliferation due to elevated intracellular cGMP levels was verified by application of the membrane-permeable cGMP analog 8-Br-cGMP and inhibition of the cGMP dependent protein kinase G by its inhibitor KT2358. Moreover, Tadalafil strongly attenuated TGFβ1-induced fibroblast-to-myofibroblast transdifferentiation. The inhibitory effect on transdifferentiation was also observed after siRNA-mediated PDE5 knockdown. As confirmed by the MEK1 inhibitor PD98059 this effect was mediated via MEK/ERK signaling.
We conclude that BPH patients might benefit from PDE5 inhibitors that inhibit stromal cell proliferation as well as TGFβ1-induced transdifferentiation processes.
Prague, Czech Republic
24 - 28 Apr 2010
European Society of Endocrinology