Epidemiological studies suggest a relationship between vitamin D deficiency and erectile dysfunction (ED). We hypothesized that vitamin D deficiency or vitamin D receptor (VDR) knockout causes ED and analysed the underlying molecular mechanisms.
Erectile function was assessed in vivo in anaesthetized male mice or rats by evaluating intracavernosal pressure (ICP) and in vitro in male Vdr-/- mice, and rat or human isolated corpora cavernosa (CCs) mounted in a myograph. Bulk RNA-sequencing (RNA-seq) transcriptomic analysis was performed in rat CCs. Vitamin D deficiency was induced in rats fed a vitamin D-free diet for 5 months.
CCs from human donors with low plasma vitamin D exhibited reduced nitric oxide (NO)-dependent erectile function. This ED was also reproduced in vitamin D-deficient rats and VDR knockout mice, in vivo and ex vivo, and is associated with penile fibrosis and reduced response to the phosphodiesterase 5 inhibitor (PDE5i) sildenafil. CCs from deficient rats show increased superoxide levels, and their impaired erectile function was restored by superoxide scavengers. Transcriptomic analysis, real-time polymerase chain reaction (RT-PCR) and Western blot showed down-regulated secretory leukocyte protease inhibitor (Slpi). Moreover, recombinant SLPI prevented superoxide-induced ED, while Slpi gene silencing led to reduced erectile function in a superoxide-dependent manner.
Vitamin D deficiency or VDR knockout reduces erectile function. We suggest that this effect is mediated by increased superoxide levels and down-regulation of SLPI. Vitamin D deficiency might be an aetiological factor for vascular ED and for the therapeutic failure of PDE5i.
British journal of pharmacology. 2025 Apr 13 [Epub ahead of print]
Miguel A Olivencia, Belén Climent, Bianca Barreira, Daniel Morales-Cano, Ana Sánchez, Argentina Fernández, Borja García-Gómez, Javier Romero-Otero, Claudia Rodríguez, Laura Moreno, Dolores Prieto, María Jesús Larriba, Angel Cogolludo, Javier Angulo, Francisco Perez-Vizcaino
Department of Pharmacology and Toxicology, School of Medicine, Complutense University of Madrid, Madrid, Spain., Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), Madrid, Spain., Department of Physiology, School of Pharmacy, Complutense University of Madrid, Madrid, Spain., Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain., Servicio de Urología, Hospital Universitario 12 de Octubre, Instituto de Investigación Hospital 12 de Octubre (imas12), Madrid, Spain., Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain.