Ageing-induced hypercontractility is related to functional enhancement of STIM/Orai and upregulation of Orai 3 in rat and human penile tissue

• Published in: Mechanisms of ageing and development Vol. 200; p. 111590
• Main Authors: Sevilleja-Ortiz, Alejandro, El Assar, Mariam, García-Rojo, Esther, García-Gómez, Borja, Fernández, Argentina, Sánchez-Ferrer, Alberto, La Fuente, José M., Romero-Otero, Javier, Rodríguez-Mañas, Leocadio, Angulo, Javier
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.12.2021
• Subjects: Aged; Ageing; Animals; Arteries - drug effects; Arteries - metabolism; Arteries - physiopathology; Calcium Channel Blockers - pharmacology; Calcium Channels - metabolism; Calcium signaling; Calcium Signaling - drug effects; Calcium Signaling - physiology; Erectile dysfunction; Erectile Dysfunction - drug therapy; Erectile Dysfunction - metabolism; Erectile Dysfunction - physiopathology; Human corpus cavernosum; Humans; Male; Muscle Contraction - drug effects; Muscle Contraction - physiology; Orai channel; Penile Erection - drug effects; Penile Erection - physiology; Penis - blood supply; Penis - drug effects; Penis - metabolism; Penis - physiopathology; Rat corpus cavernosum; Rats; Stromal Interaction Molecule 1 - metabolism; Vascular function; Vasoconstrictor Agents - pharmacology; Vasodilator Agents - pharmacology; Calcium signaling; Human corpus cavernosum; Ageing; Rat corpus cavernosum; Erectile dysfunction; Vascular function; Orai channel
• DOI: 10.1016/j.mad.2021.111590
• ISSN: 0047-6374; 1872-6216

[Display omitted] •Role of STIM/Orai calcium entry system in vascular ageing is not elucidated.•Ageing is related to Orai 3 upregulation in cavernosal tissues from rats and humans.•STIM/Orai inhibition reverses hypercontractility of aged rat and human penile smooth muscle.•Enhanced STIM/Orai signalling has a role in ageing-related vascular alterations.•STIM/Orai inhibition could reduce impact of ageing on vascular and erectile function. The role of STIM/Orai calcium entry system on vascular ageing has not been elucidated. We aimed to evaluate the influence of ageing on STIM/Orai signalling and its role on ageing-induced alterations of contractile function in rat corpus cavernosum (RCC) and human penile resistance arteries (HPRA) and corpus cavernosum (HCC). RCC was obtained from 3 months-old and 20 months-old animals. HPRA and HCC were obtained from organ donors of varied ages without history of erectile dysfunction. Aging was associated with enhanced norepinephrine (NE)- and thromboxane analogue (U46619)-induced contractions in RCC which were significantly inhibited by the STIM/Orai inhibitor, YM-58483 (20 μM). Other STIM/Orai inhibitor, 2-aminoethyldiphenylborate also reduced NE-induced contractions in RCC from aged rats. YM-58483 significantly reduced neurogenic contractions and potentiated neurogenic relaxations in RCC from aged rats. In HCC and HPRA, NE-induced contractions were significantly enhanced in older subjects (>65 years-old) but YM-58483 completely reversed ageing-related hypercontractility. Ageing did not modify STIM-1 and Orai1 protein expressions but Orai3 was significantly overexpressed in cavernosal tissue from old rats and older subjects. Contribution of STIM/Orai to cavernosal contraction increases with ageing together with increased expression of Orai3. Orai inhibition could be a potential therapeutic strategy to reduce ageing-related impact on vascular/erectile function.