Cystathionine γ Lyase Deletion Enhances Corpus Cavernosum Contraction via Thromboxane A2 and Neurogenic Pathways Without Affecting Endothelial Function

Abstract

Cystathionine {gamma}-lyase (CSE) produces hydrogen sulfide (H2S), a vasodilator critical for vascular function. While its systemic effects are well-documented, its role in erectile physiology remains unclear. This study investigated the impact of CSE deletion on vascular and erectile tissue reactivity. We hypothesized that CSE knockout (CSE-KO) mice would exhibit endothelial dysfunction. A total of 22 CSE-KO and 22 age-matched wild-type (WT) controls were studied at one year of age. The internal iliac artery (IIA), internal pudendal artery (IPA), and corpus cavernosum (CC) were harvested for ex vivo functional assessments using tissue, wire, and pressure myography. Vasoconstriction was evaluated using phenylephrine, endothelin-1, U-46619, and electrical field stimulation (EFS). Endothelium-dependent relaxation was assessed using acetylcholine (ACh) and flow-mediated dilation, while endothelium-independent relaxation was evaluated using sodium nitroprusside (SNP). Sodium sulfide (Na2S) was used to assess H2S-mediated dilation. Non-adrenergic, non-cholinergic (NANC) transmission was evaluated using EFS. No significant differences were observed in ACh-, SNP-, or flow-mediated relaxation, although CSE-KO mice demonstrated impaired NANC-nerve mediated relaxation in the CC. Moreover, CSE-KO mice exhibited significantly enhanced CC contraction in response to U-46619 and EFS, suggesting increased vascular resistance in the end organ CC rather than the pre-penile arteries. Histological analysis revealed no significant structural or fibrotic remodeling in any tissue, although there was a trend toward increased collagen deposition in the IIA and IPA. These findings indicate that chronic CSE deficiency does not impair endothelial function but alters neurogenic control and increases vasoconstrictive sensitivity specifically in the CC, potentially predisposing to erectile dysfunction. NEW & NOTEWORTHYThis study highlights the critical role of hydrogen sulfide (H2S) in erectile physiology by demonstrating that CSE deletion does not impair endothelial function but significantly enhances neurogenic and thromboxane A2 receptor-induced vasoconstriction specifically in the corpus cavernosum (CC). These findings suggest that endogenous H2S modulates neurovascular control of erection. Its deficiency predisposes the erectile system to heightened vascular resistance predominantly in the end organ, providing novel insights into the vascular mechanisms underlying erectile dysfunction.