Wendt Trevor S, Ansar Saema, Gonzales Rayna J
Department of Basic Medical Sciences, University of Arizona, Phoenix, AZ, United States.
Applied Neurovascular Research, Neurosurgery, Department of Clinical Sciences, Lund University, Lund, Sweden.
Front Physiol. 2024 Nov 5;15:1471272. doi: 10.3389/fphys.2024.1471272. eCollection 2024.
Elevated plasma levels of oxidized low-density lipoprotein (oxLDL) are a risk factor and key component that accelerates and worsens cardiovascular disease fueling inflammation, plaque buildup and vascular damage. OxLDL can elicit its detrimental action via lectin-like oxLDL receptor 1 (LOX-1). In this study, we determined whether oxLDL, via LOX-1, alters aortic vascular reactivity and determined if sex and age differences exist. Thoracic aortic endothelium-intact or -denuded ring segments were isolated from 7 to 12 months old intact C57BL/6J female and male mice and pre-incubated with oxLDL (50ug/dL; 2 h). Using wire myography, cumulative concentration-response curves to phenylephrine (PE) were generated to determine contractile responses. From these curves, the EC50 was determined and used to contract rings to assess acetylcholine (ACh) dependent relaxation. Calculated aortic stiffness and remodeling were also assessed. BI-0115 (10 M; selective LOX-1 inhibitor) was used to determine LOX-1 dependence. We observed differential sex, age, endothelial cell, and LOX-1 dependent alterations to the efficacy of PE-induced contractile responses and ACh-mediated vasorelaxation in thoracic aortic rings following oxLDL exposure. Additionally, we observed a distinct sex and age effect on thoracic aortic stiffness following exposure to oxLDL. There was also a sex effect on calculated vessel diameter, as well as an age effect on oxLDL-mediated aortic remodeling that was LOX-1 dependent. Thus, LOX-1 inhibition and the resulting attenuation of oxLDL/endothelial-mediated alterations in aortic function suggests that there are differential sex differences in the role of oxLDL/LOX-1 in the thoracic aorta of middle-aged male and female mice. NEW and NOTEWORTHY. We investigated the effects of oxLDL via the LOX-1 receptor on murine thoracic aortic vasoreactivity, stiffness, and remodeling across age and sex. Acute exposure to oxLDL led to altered vasoreactivity, endothelial dysfunction, and changes in aortic stiffness and remodeling. These effects were in-part age, sex, endothelial, and LOX-1 dependent. This study reveals potential complex interactions in oxLDL/LOX-1-mediated vascular responses that could serve as potential therapeutic intervention for vascular diseases such as atherosclerosis and stroke.
氧化型低密度脂蛋白（oxLDL）的血浆水平升高是加速和恶化心血管疾病的危险因素及关键组成部分，会加剧炎症、斑块形成和血管损伤。OxLDL可通过凝集素样oxLDL受体1（LOX-1）引发其有害作用。在本研究中，我们确定oxLDL是否通过LOX-1改变主动脉血管反应性，并确定是否存在性别和年龄差异。从7至12月龄的完整C57BL/6J雌性和雄性小鼠中分离出胸主动脉内皮完整或去内皮的环段，并用oxLDL（50μg/dL；2小时）进行预孵育。使用线肌张力测定法，生成对去氧肾上腺素（PE）的累积浓度-反应曲线以确定收缩反应。从这些曲线中确定EC50，并用于收缩环以评估乙酰胆碱（ACh）依赖性舒张。还评估了计算得出的主动脉僵硬度和重塑情况。使用BI-0115（10μM；选择性LOX-1抑制剂）来确定对LOX-1的依赖性。我们观察到，在oxLDL暴露后，胸主动脉环中PE诱导的收缩反应和ACh介导的血管舒张功效存在性别、年龄、内皮细胞和LOX-1依赖性差异。此外，我们观察到oxLDL暴露后对胸主动脉僵硬度有明显的性别和年龄效应。对计算得出的血管直径也有性别效应，对oxLDL介导的主动脉重塑有年龄效应，且该效应依赖于LOX-1。因此，LOX-1抑制以及由此导致的oxLDL/内皮介导的主动脉功能改变的减弱表明，oxLDL/LOX-1在中年雄性和雌性小鼠胸主动脉中的作用存在不同的性别差异。新内容及值得注意之处。我们研究了通过LOX-1受体的oxLDL对不同年龄和性别的小鼠胸主动脉血管反应性、僵硬度和重塑的影响。急性暴露于oxLDL会导致血管反应性改变、内皮功能障碍以及主动脉僵硬度和重塑的变化。这些效应部分依赖于年龄、性别、内皮细胞和LOX-1。本研究揭示了oxLDL/LOX-1介导的血管反应中潜在的复杂相互作用，这可能为动脉粥样硬化和中风等血管疾病提供潜在的治疗干预措施。
