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

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: 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.