Ischemia and oxidative stress are increasingly implicated in lower urinary tract symptoms/dysfunction (LUTS/D), including overactive bladder (OAB), bladder outlet obstruction (BOO), bladder pain syndrome (BPS), chronic pelvic pain syndrome (CPPS), and detrusor underactivity (DU). However, the precise molecular pathways linking ischemia-induced oxidative injury to functional bladder deterioration remain poorly characterized and research is fragmented across disciplines/disease states.[1] This scoping review aimed to systematically map current literature on ischemia and oxidative stress in LUTS by: (1) cataloguing animal models used to induce ischemic and oxidative stress conditions; (2) summarizing biomarkers of oxidative stress; (3) describing the pathophysiological mechanisms linking ischemia to LUTD; and (4) evaluating therapeutic strategies under investigation.

A scoping review was conducted adhering to the PRISMA-ScR checklist. Comprehensive search strategies were developed in collaboration with a medical librarian and executed in PubMed/MEDLINE, Web of Science, Embase, and Scopus. Each citation was required to contain at least one term related to LUTS/ and one related to ischemia and/or oxidative stress. In vitro, ex vivo, animal, and human clinical studies were included. Exclusion criteria were benign prostatic enlargement without the context of ischemia and purely neurogenic LUTD. Two reviewers independently screened titles, abstracts, and full texts, with conflicts resolved by a third reviewer. Data extraction was performed by five reviewers using a standardized template and verified for consistency.

164 studies met inclusion criteria. Figure 1 summarizes study/manuscript characteristics. The majority focused on OAB/detrusor overactivity (DO), followed by BOO, BPS/CPPS, DUA, and general LUTS. Therapeutic studies were most common, followed by mechanistic investigations. Animal models (particularly rat and mouse models) predominated. Chronic bladder ischemia was most commonly modeled through urinary outlet obstruction and bilateral iliac artery injury, and oxidative stress was induced using intravesical chemoirritants. There was significant heterogeneity in oxidative stress biomarkers; the most frequently measured were 8-hydroxy-2’-deoxyguanosine, malondialdehyde, 3-nitrotyrosine, catalase, and superoxide dismutase. In human studies, urinary biomarkers including 8-isoprostane, total antioxidant capacity, and inflammatory cytokines showed associations with DO, DU, and OAB, with variable discriminatory utility. Pathophysiological mechanisms included bladder sensitization via transient receptor potential channels and purinergic receptors, neurodegeneration, apoptosis (via Nrf2, PI3K/Akt, and NF-κB pathways), mitochondrial/endoplasmic reticulum stress, inflammation, and fibrosis. Severity and duration of ischemia influenced whether bladder pathophysiology exhibited overactivity or progressed to underactivity. Therapeutic investigations encompassed vasoactive agents (PDE5 inhibitors, α1-adrenoceptor antagonists), antioxidants, phytochemicals, hormonal therapies, neuromodulators, and procedural interventions. (Figure 2)  In animal models, these consistently improved bladder function and reduced oxidative stress. Human trials were limited but showed improvements with tadalafil, tamsulosin, and dutasteride.

Substantial overlap exists in the cellular pathways, animal models, and therapeutic approaches across different LUTS/D conditions, reflecting shared ischemia-driven stress mechanisms. This overlap complicates the identification of condition-specific biomarkers. DU remains understudied despite biomarker evidence suggesting it may represent the end-stage of chronic ischemia, evolving from DO through a mixed DO-DU state. The heterogeneity in experimental models, oxidative stress endpoints, and outcome measures across studies limits direct comparisons and clinical translation.

Ischemia and oxidative stress contribute to LUTS/D through a complex interplay of inflammatory, neurodegenerative, apoptotic, and sensitization pathways affecting both the detrusor and its innervation. Key knowledge gaps include the pathophysiology and therapeutic targeting of DU, standardization of biomarker panels for clinical translation, validation of non-invasive bladder perfusion monitoring in humans, and translational evaluation of the numerous antioxidant and phytochemical agents that have shown preclinical promise. Future research should prioritize standardized experimental endpoints and adequately powered human studies to bridge the gap between preclinical findings and clinical application.

Speich JE, Tarcan T, Hashitani H, Vahabi B, McCloskey KD, Andersson KE, Wein AJ, Birder LA. Are oxidative stress and ischemia significant causes of bladder damage leading to lower urinary tract dysfunction? Report from the ICI-RS 2019. Neurourol Urodyn. 2020 Jul;39 Suppl 3(Suppl 3):S16-S22. doi: 10.1002/nau.24313.