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. 2025 Aug;182(15):3669-3687.
doi: 10.1111/bph.70034. Epub 2025 Apr 13.

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

Miguel A Olivencia  1   2   3 , Belén Climent  2   3   4 , Bianca Barreira  1   2   3 , Daniel Morales-Cano  1   2   3 , Ana Sánchez  4 , Argentina Fernández  5   6 , Borja García-Gómez  7 , Javier Romero-Otero  7 , Claudia Rodríguez  4 , Laura Moreno  1   2   3 , Dolores Prieto  4 , María Jesús Larriba  8   9   10 , Angel Cogolludo  1   2   3 , Javier Angulo  5   6 , Francisco Perez-Vizcaino  1   2   3
Affiliations

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

Miguel A Olivencia et al. Br J Pharmacol. 2025 Aug.

Abstract

Background and purpose: 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.

Experimental approach: 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.

Key results: 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.

Conclusion and implications: 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.

Keywords: SLPI; corpora cavernosa; erectile dysfunction; nitric oxide; superoxide; vitamin D deficiency.

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