Endogenous urotensin–II induced-penile erection trhough eNOS phosphorylation in human corpus cavernosum

Urotensin II (U-II) is a cyclic peptide originally isolated from the neurosecretory system of the teleost fish and subsequently found in other species, including man. U-II was identified as the natural ligand of a G-protein coupled receptor (GPR 14), namely UT receptor (Romanic et al., 1999). To date, the source of U-II production in the human body remains to be elucidated. Both U-II and UT receptor are expressed widely within the cardiovascular system, and the expression is up-regulated in human cardiovascular disease, including congestive heart failure, hypertension, type II diabetes and diabetic nephropathy (Russell et al., 2004; Maguire et al., 2000).Recent evidence indicates the involvement of U-II/UT pathway in penile function in human, but the molecular mechanism is still unclear (d'Emmanuele di Villa Bianca et al., 2010).The aim of this study was to investigate the mechanism(s) of U-II-induced relaxation in human tissue and its relationship with L-arginine/Nitric oxide (NO) pathway. The human corpus cavernosum (HCC) was obtained from male to female surgical procedure. U-II mRNA by quantitative RT-PCR was assessed in human tissue. Nitrite content, as index of NO production, was fluorometrically determined in tissues challenged with U-II or vehicle. Western blots for phosphorylated-eNOS(Serine 1177) and eNOS were evaluated in HCC incubated with U-II (10 µM). HCC precontracted strips were challenged with U-II (0.1 nM–10 µM) in presence either wortmannin or geldanamycin, inhibitors of eNOS phosphorylation and Hsp90 coupling, respectively. A co-immunoprecipitation study between eNOS and UT receprtor was also performed following stimulation with U-II or vehicle. U-II as mRNA is expressed in HCC and promotes NO production. Wortmannin or geldanamycin inhibited significantly U-II-induced relaxation in HCC strips. Additionally, U-II significantly increased eNOS phosphorylation/eNOS ratio, supporting the functional study. UT receptor and eNOS co-immunoprecipitated following U-II challenge of HCC. In conclusion, U-II is endogenously synthesized and locally released in HCC. Thepro-erectile effect of U-II is strictly dependent upon NO generation by eNOSphosphorylation and Hsp90 recruitment. Thus, UII/UT pathway may contribute to the maintenance of full penile erection. Romanic (1999). Nature. 401, 282–286. Maguire (2000). Br J Pharmacol. 131, 441–446. Russell (2004). Pharmacol Ther 103, 223-243. d'Emmanuele di Villa Bianca (2010). J Sex Med.7, 1778-1786.