Azeez Tooyib A, Pierre Clifford J, Ihrig Colin M, Chelko Stephen P, Muller-Delp Judy M, La Favor Justin D
bioRxiv. 2025 May 22:2025.05.17.654668. doi: 10.1101/2025.05.17.654668.
Cystathionine γ-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 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 & NOTEWORTHY: This 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.
胱硫醚γ-裂解酶（CSE）可产生硫化氢（H₂S），这是一种对血管功能至关重要的血管舒张剂。虽然其全身作用已得到充分证明，但其在勃起生理学中的作用仍不清楚。本研究调查了CSE缺失对血管和勃起组织反应性的影响。我们假设CSE基因敲除（CSE-KO）小鼠会出现内皮功能障碍。在一岁时对总共22只CSE-KO小鼠和22只年龄匹配的野生型（WT）对照小鼠进行了研究。采集髂内动脉（IIA）、阴部内动脉（IPA）和海绵体（CC），使用组织、线和压力肌动描记法进行功能评估。使用去氧肾上腺素、内皮素-1、U-46619和电场刺激（EFS）评估血管收缩。使用乙酰胆碱（ACh）和血流介导的舒张来评估内皮依赖性舒张，而使用硝普钠（SNP）评估非内皮依赖性舒张。使用硫化钠（Na₂S）评估H₂S介导的舒张。使用EFS评估非肾上腺素能、非胆碱能（NANC）传递。虽然CSE-KO小鼠在CC中表现出NANC神经介导的舒张受损，但在ACh、SNP或血流介导的舒张方面未观察到显著差异。此外，CSE-KO小鼠对U-46619和EFS的反应表现出CC收缩显著增强，表明终末器官CC而非阴茎前动脉的血管阻力增加。组织学分析显示，任何组织均无明显的结构或纤维化重塑，尽管IIA和IPA中有胶原沉积增加的趋势。这些发现表明，慢性CSE缺乏不会损害内皮功能，但会改变神经源性控制，并特别增加CC中的血管收缩敏感性，可能易患勃起功能障碍。
本研究通过证明CSE缺失不会损害内皮功能，但会显著增强神经源性和血栓素A2受体诱导的血管收缩，特别是在海绵体（CC）中，突出了硫化氢（H₂S）在勃起生理学中的关键作用。这些发现表明内源性H₂S调节勃起的神经血管控制。其缺乏使勃起系统易患主要在终末器官中的血管阻力增加，为勃起功能障碍的血管机制提供了新的见解。
