Vitamin D deficiency induces erectile dysfunction: Role of superoxide and Slpi.

Apr 14, 2025

Experts: 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

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.

© 2025 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

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ABOUT THE EXPERTS

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

Miguel A Olivencia

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.

Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.

Belén Climent

Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), Madrid, Spain.

Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.

Department of Physiology, School of Pharmacy, Complutense University of Madrid, Madrid, Spain.

Bianca Barreira

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.

Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.

Daniel Morales-Cano

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.

Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.

Ana Sánchez

Department of Physiology, School of Pharmacy, Complutense University of Madrid, Madrid, Spain.

Argentina Fernández

Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain.

Servicio de Histología-Investigación, Unidad de Investigación Traslacional en Cardiología (IRYCIS-UFV), Hospital Universitario Ramón y Cajal, Madrid, Spain.

Borja García-Gómez

Servicio de Urología, Hospital Universitario 12 de Octubre, Instituto de Investigación Hospital 12 de Octubre (imas12), Madrid, Spain.

Javier Romero-Otero

Servicio de Urología, Hospital Universitario 12 de Octubre, Instituto de Investigación Hospital 12 de Octubre (imas12), Madrid, Spain.

Claudia Rodríguez

Department of Physiology, School of Pharmacy, Complutense University of Madrid, Madrid, Spain.

Laura Moreno

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.

Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.

Dolores Prieto

Department of Physiology, School of Pharmacy, Complutense University of Madrid, Madrid, Spain.

María Jesús Larriba

Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain.

Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain.

Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid, Spain.

Angel Cogolludo

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.

Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.

Javier Angulo

Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain.

Servicio de Histología-Investigación, Unidad de Investigación Traslacional en Cardiología (IRYCIS-UFV), Hospital Universitario Ramón y Cajal, Madrid, Spain.

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.

Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.