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We hypothesized that vitamin D deficiency or vitamin D receptor (VDR) knockout causes ED and analysed the underlying molecular mechanisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Erectile function was assessed in vivo in anaesthetized male mice or rats by evaluating intracavernosal pressure (ICP) and in vitro in male <jats:italic>Vdr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice, and rat or human isolated corpora cavernosa (CCs) mounted in a myograph. Bulk RNA\u2010sequencing (RNA\u2010seq) transcriptomic analysis was performed in rat CCs. Vitamin D deficiency was induced in rats fed a vitamin D\u2010free diet for 5\u2009months.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>CCs from human donors with low plasma vitamin D exhibited reduced nitric oxide (NO)\u2010dependent erectile function. This ED was also reproduced in vitamin D\u2010deficient 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\u2010time polymerase chain reaction (RT\u2010PCR) and Western blot showed down\u2010regulated secretory leukocyte protease inhibitor (<jats:italic>Slpi<\/jats:italic>). Moreover, recombinant SLPI prevented superoxide\u2010induced ED, while <jats:italic>Slpi<\/jats:italic> gene silencing led to reduced erectile function in a superoxide\u2010dependent manner.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Vitamin D deficiency or VDR knockout reduces erectile function. We suggest that this effect is mediated by increased superoxide levels and down\u2010regulation of SLPI. Vitamin D deficiency might be an aetiological factor for vascular ED and for the therapeutic failure of PDE5i.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.70034","type":"journal-article","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T00:49:36Z","timestamp":1744591776000},"page":"3669-3687","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Vitamin D deficiency induces erectile dysfunction: Role of superoxide and Slpi"],"prefix":"10.1111","volume":"182","author":[{"given":"Miguel A.","family":"Olivencia","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Medicine Complutense University of Madrid  Madrid Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Respiratorias (CIBERES)  Madrid Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Gregorio Mara\u00f1\u00f3n (IiSGM)  Madrid 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