Bianca BarreiraFrancisco Perez-VizcainoOlivencia Plaza, Miguel ÁngelCliment Flórez, BelénMorales Cano, DanielMoreno Gutiérrez, LauraRodríguez Prados, ClaudiaPrieto Ocejo, DoloresCogolludo Torralba, Ángel LuisPérez Vizcaíno, Francisco2026-01-132026-01-132025-08-01Olivencia MA, Climent B, Barreira B, Morales-Cano D, Sánchez A, Fernández A, García-Gómez B, Romero-Otero J, Rodríguez C, Moreno L, Prieto D, Larriba MJ, Cogolludo A, Angulo J, Perez-Vizcaino F. Vitamin D deficiency induces erectile dysfunction: Role of superoxide and Slpi. Br J Pharmacol. 2025 Aug;182(15):3669-3687. doi: 10.1111/bph.70034. Epub 2025 Apr 13. PMID: 40222751.10.1111/bph.70034https://hdl.handle.net/20.500.14352/130083Background 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.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/journal articlehttps://dx.doi.org/10.1111/bph.70034https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.70034open access61SLPICorpora cavernosaErectile dysfunctionNitric oxideSuperoxideVitamin D deficiencyCiencias Biomédicas32 Ciencias Médicas