SECUAH 2021

dianas | Vol 9 No 1 | marzo 2020 | e202003

Aging increases contribution of Orai channels to contractile tone in corpus cavernosum. Therapeutic potential in erectile dysfunction.

Alejandro Sevilleja-Ortiz, Mariam El Assar, Argentina Fernández, Borja García-Gómez, Ester García-Rojo, José Medina-Polo, Manuel Alonso-Isa, Jose María La Fuente, Leocadio Rodríguez-Mañas, Javier Romero-Otero, Javier Angulo

Hospital Universitario Ramón y Cajal (Ctra. de Colmenar Viejo km. 9,100 28034 Madrid)

alex.sevilleja9335@gmail.com

V Congreso de Señalización Celular, SECUAH 2020.
16-18 de marzo, 2020. Universidad de Alcalá. Alcalá de Henares, Madrid. España.

Keywords: corpus cavernosum; human penile arteries; aging; erectile dysfunction; Orai channels; store-operated calcium entry;

Abstract

Altered regulation of penile smooth muscle tone accounts for erectile dysfunction (ED). Contribution of calcium Orai channels to contractile responses in penile smooth muscle has been proposed. Since aging is a main risk factor for ED, the aim was to evaluate the influence of aging on contribution of Orai channels to rat and human penile tissue contraction at functional and expression level. The impact of ED on STIM/Orai signaling was also analyzed in human penile vascular tissues. Rat corpus cavernosum (RCC) was obtained from young (3months-old) and aged (20 months-old) animals. Human penile resistance arteries (HPRA) and corpus cavernosum (HCC) were dissected from cavernosal specimens from 21 organ donors without history of ED (No ED) which were divided into younger than 65 years (43.5±2.8 years, n=16) and older than 65 years (74.2±3.5 years, n=5) and from 19 ED patients undergoing penile prosthesis insertion. Tissues were functionally evaluated in wire myographs and organ chambers.The effect of Orai channel inhibitor, YM-58483 (YM) (20 µM) was evaluated on contractile responses in rat and human penile tissues. The expression of Orai channels in RCC and HCC was determined by Western blot and immunofluorescence. NE-induced contractions in RCC from young rats were not significantly modified by YM (133.1±3.1% vs. 127.9±10.2% of K+-induced contraction, respectively). In contrast, the significantly increased NE-induced contractions in aged rats were clearly inhibited by YM (252.4±22.5% vs.171.9±7.2%, p<0.01). YM significantly reduced neurogenic and thromboxane-induced contractions in RCC from aged rats. In HCC, NE-induced contractions were significantly enhanced in old subjects (176.7±17.5% vs. 130.9±9.4%, p<0.05). The treatment with YM only significantly reduced contractile responses in HCC from old subjects, yielding similar contractions to those exhibited by younger subjects (103.8±11.6% in younger vs. 108.1±10.6% in older). Orai3 channel subtype was significantly overexpressed in RCC from old rats and in HCC from older subjects. Inhibition of Orai channels with YM significantly reduced NE-induced contractions in both HCC and HPRA (141.0±15.0% vs. 88.2±17.4%, p<0.01 and 136.7±9.1% vs. 85.7±7.3%, p<0.01, respectively) and enhanced neurogenic relaxations of HCC from ED patients. Expression of Orai1 and Orai3 was significantly increased in HCC from ED patients. Contribution of Orai channels to cavernosal contraction increases with aging and is paralleled by increased expression of Orai3 channel. Orai signaling in human penile tissue is also enhanced at functional and expression levels in ED. Orai inhibition is a potential therapeutic strategy to reduce penile smooth muscle contraction in aging and ED.