Epigenetic and DNA-repair programs in corpus cavernosum endothelium: genome stability and erectile dysfunction

Abstract

Erectile dysfunction (ED) is increasingly recognized as a vascular disorder in which endothelial nitric oxide synthase (eNOS)-dependent signaling is disrupted early and may precede overt cardiovascular disease. In vasculogenic and endothelial dysfunction-dominant forms of ED, accumulating evidence suggests that epigenetic regulation and genome-maintenance pathways contribute to cavernosal endothelial vulnerability. In this review, we synthesize data linking locus-specific DNA methylation—particularly at NOS3/eNOS-related regions—to reduced nitric oxide bioavailability and impaired cavernosal relaxation, while also examining how DNA repair pathways and the DNA damage response may shape endothelial phenotype under oxidative, hypoxic, metabolic, and inflammatory stress. Available evidence supports roles for base excision repair, homologous recombination, PARP-associated signaling, and broader genome-maintenance mechanisms in modulating endothelial resilience, although the strength of support is not uniform across pathways. Direct ED-related evidence is strongest for methylation-associated dysregulation of nitric oxide signaling and for DNA damage-associated impairment in diabetic or radiation-related cavernosal injury models, whereas substantial parts of the proposed methylation–DNA repair–genome stability axis are still inferred from broader vascular and endothelial biology rather than from matched human cavernosal datasets. Recent human single-cell studies of the corpus cavernosum have strengthened the biological rationale for this framework by demonstrating marked cellular and microenvironmental remodeling in diseased tissue, but they do not directly quantify DNA methylation status or pathway-specific DNA repair capacity. Clinically, current practice can phenotype vascular ED using hemodynamic tools, yet standardized approaches for directly assessing methylation-associated repression, narrowed DNA repair reserve, or genome-instability-related stress in human cavernosal tissue remain lacking. Addressing this gap may improve biological stratification and support more mechanism-informed translational studies in ED.

Keywords

Erectile dysfunction / Corpus cavernosum endothelium / DNA methylation / DNA repair / Genome instability

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RIGHTS & PERMISSIONS

Shenzhen University School of Medicine; Fondazione Istituto FIRC di Oncologia Molecolare