Gómez Del Val Alfonso, Sánchez Ana, Freire-Agulleiro Óscar, Martínez María Pilar, Muñoz Mercedes, Olmos Lucia, Medina Javier Sáenz, Comerma-Steffensen Simon Gabriel, Simonsen Ulf, Rivera Luis, López Miguel, Contreras Cristina, Prieto Dolores
Department of Physiology, Madrid Complutense University, Madrid, Spain.
NeurObesity Group, Department of Physiology, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Santiago de Compostela, Spain.
Free Radic Biol Med. 2025 Mar 16;230:222-233. doi: 10.1016/j.freeradbiomed.2025.02.004. Epub 2025 Feb 8.
Erectile dysfunction (ED) is considered an early manifestation of cardiovascular disease (CVD), endothelial dysfunction being the link between CVD and vasculogenic ED. Mitochondrial reactive oxygen species (mtROS) have been involved in the vascular complications of metabolic disorders. The aim of this study was to assess the impact of obesity on endothelial function, redox metabolism and mitochondrial bioenergetics of penile erectile tissue.
Wistar rats were fed a high-fat diet (HFD) or standard diet (STD), and penile vascular function was assessed in microvascular myographs. mtROS levels were measured by mitoSOX (O) and Amplex Red (HO) fluorimetry, and the effect of the mitochondrial antioxidant mitoTempo on endothelium-dependent relaxations was tested. Mitochondrial respiration of intact microarteries was assessed with an Agilent Seahorse XF Pro analyzer, and the expression of mitochondria redox regulators was analysed by Western blot.
Endothelium-dependent relaxations to acetylcholine (ACh) and to the mitoK channel activator BMS191095 were reduced in penile arteries from HFD. mtROS levels were significantly increased and associated with upregulation of the endothelial NADPH oxidase 4 (Nox4) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in HFD erectile tissue. MitoTempo inhibited endothelial relaxations in control and HFD penile arteries. The bioenergetic profile was significantly reduced in HFD penile arteries compared to STD rats.
Mitochondrial dysfunction with impaired bioenergetics and reduced mitoK channel-mediated relaxation underlie endothelial and vascular dysfunction of erectile tissue in obesity, despite a compensatory mechanism that enhances Nox4-derived endothelial vasodilator mtROS. Therapeutic strategies aimed to stabilize mitochondria could restore redox balance and improve mitochondrial bioenergetics thus preventing oxidative stress and vascular dysfunction underlying metabolic disease associated ED.
勃起功能障碍（ED）被认为是心血管疾病（CVD）的早期表现，内皮功能障碍是CVD与血管源性ED之间的联系。线粒体活性氧（mtROS）参与了代谢紊乱的血管并发症。本研究的目的是评估肥胖对阴茎勃起组织的内皮功能、氧化还原代谢和线粒体生物能量学的影响。
给Wistar大鼠喂食高脂饮食（HFD）或标准饮食（STD），并在微血管肌动描记器中评估阴茎血管功能。通过mitoSOX（O）和Amplex Red（HO）荧光法测量mtROS水平，并测试线粒体抗氧化剂mitoTempo对内皮依赖性舒张的影响。使用安捷伦海马XF Pro分析仪评估完整微动脉的线粒体呼吸，并通过蛋白质印迹法分析线粒体氧化还原调节剂的表达。
HFD喂养的大鼠阴茎动脉对乙酰胆碱（ACh）和线粒体钾通道激活剂BMS191095的内皮依赖性舒张降低。HFD勃起组织中的mtROS水平显著升高，并与内皮型NADPH氧化酶4（Nox4）和过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）的上调相关。MitoTempo抑制对照和HFD阴茎动脉的内皮舒张。与STD大鼠相比，HFD阴茎动脉的生物能量学特征显著降低。
尽管存在增强Nox4衍生的内皮血管舒张性mtROS的代偿机制，但肥胖状态下勃起组织的内皮和血管功能障碍的基础是线粒体功能障碍，生物能量学受损以及线粒体钾通道介导的舒张减少。旨在稳定线粒体的治疗策略可以恢复氧化还原平衡并改善线粒体生物能量学，从而预防与代谢疾病相关的ED的氧化应激和血管功能障碍。
