The serotonergic system in periaortic fat regulates regional aortopathy development

主动脉周围脂肪中的血清素能系统调节区域主动脉病的发展

• 批准号: 10651042
• 负责人: Lisa A Cassis
• 金额: $ 59.52万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651042
• 关键词: Abdomen; Adipocytes; Anatomy; Aneurysm; Angiotensin II; Aorta; Aortitis; Area; Brown Fat; Calcium; Catabolism; Cations; Cd68; Chest; Complement; Dangerousness; Data; Deamination; Development; Diffuse; Disease; Elements; Environmental Risk Factor; Enzymes; Exposure to; Fatty acid glycerol esters; Functional disorder; Genetic; Human; Hydrogen Peroxide; In Vitro; Inflammasome; Inflammation; Infusion procedures; Ion Channel Gating; Left; Length; Ligands; Link; Lipopolysaccharides; Macrophage; Mediating; Mitochondria; Modeling; Monoamine Oxidase; Mus; Mutant Strains Mice; Myelogenous; Necrosis Induction; Neurons; Neurotransmitters; Peripheral; Production; Protein Isoforms; Reactive Oxygen Species; Regulation; Reporting; Respiration; Risk; Role; Rupture; Serotonergic System; Serotonin; Sex Chromosomes; Side; Source; Stimulus; Thermogenesis; Thoracic aorta; Tropisetron; Tryptophan; Tryptophan 5-monooxygenase; Tunica Adventitia; Vascular Diseases; abdominal aorta; abdominal fat; antagonist; aortic arch; differential expression; in vivo; male; mitochondrial dysfunction; nerve supply; neural; new therapeutic target; novel; receptor; recruit; regional difference; sex; therapeutic target; uptake

Aortopathies are dangerous vascular diseases with no known therapy that can occur in different aortic regions depending on genetic and environmental factors. Periaortic fat surrounding different regions of the aorta is composed of different adipocyte and neuronal elements and has been reported to be associated with human aortopathies. Preliminary data demonstrate levels of serotonin (5HT) in periaortic fat differ according to aortic region, and similarly, there is differential expression of the 5HT3 receptor (Htr3) along the aortic length. Infusion of angiotensin II (AngII), a well-known stimulus of regional aortopathies, was associated with regulation of 5HT levels in thoracic brown periaortic, but not white abdominal periaortic fat, and AngII promoted neuronal release of 5HT from thoracic aortic sections with adherent periaortic fat. Moreover, J774 macrophages responded to 5HT to promote inflammation and altered basal mitochondrial respiration through an Htr3-mediated mechanism. Notably, administration of an Htr3 antagonist to AngII-infused mice abolished regional aortopathies. We hypothesize that periaortic fat-derived 5HT acts at Htr3 on resident or recruited macrophages within periaortic fat to promote aortic adventitial inflammation and stimulate mitochondrial reactive oxygen species production, contributing to AngII-induced aortopathies. An ability of periaortic fat- derived 5HT and macrophage Htr3 to influence the aortic adventitia is likely due to the absence of an anatomic barrier. Moreover, we hypothesize that regional differences in periaortic fat-derived production of 5HT, its regulation by AngII, and its ability to stimulate macrophage Htr3 contribute to regional differences in AngII- induced aortopathies. Aim 1 will define the impact of regional differences in the synthesis of 5HT and its regulation by AngII in periaortic fat on the regional development and progression of AngII-induced aortopathies. Aim 2 will define mechanisms of macrophage Htr3 on regional development of AngII-induced aortopathies and investigate mechanisms of 5HT/Htr3 to promote macrophage inflammation and mitochondrial dysfunction. Results from these studies will identify a novel role for periaortic fat, through a 5HT/Htr3 mechanism, on regional aortopathy development and may identify new therapeutic targets optimized to specific regional aortopathies.

动脉病变是危险的血管疾病，目前尚无已知的治疗方法，可发生在不同的主动脉区域。 取决于遗传和环境因素。环绕在主动脉不同区域的腹主动脉周围脂肪 由不同的脂肪细胞和神经细胞组成，据报道与人类 大动脉病变。初步数据显示，主动脉周围脂肪中的5-羟色胺(5-HT)水平因主动脉不同而不同 同样，5HT3受体(Htr3)在主动脉长度上也有不同的表达。 血管紧张素II(AngII)的输注是一种众所周知的区域性主动脉病变的刺激因素，与 调节胸廓棕色腹主动脉周围脂肪的5-羟色胺水平，但不调节白色腹主动脉周围脂肪，并促进血管紧张素转换酶Ⅱ的表达 伴有腹主动脉周围脂肪粘连的胸主动脉切片5-羟色胺的神经元释放。此外，J774 巨噬细胞对5-羟色胺的反应通过促进炎症和改变线粒体的基础呼吸 Htr3介导的机制。值得注意的是，给注射了血管紧张素转换酶的小鼠注射Htr3拮抗剂的做法被废除 局部大动脉病变。我们假设腹主动脉周围脂肪衍生的5-羟色胺作用于常住或招募的Htr3。 腹主动脉周围脂肪中的巨噬细胞促进主动脉外膜炎症和刺激线粒体 活性氧的产生，促进血管紧张素转换酶诱导的动脉病变。腹主动脉周围脂肪的能力- 衍生的5-羟色胺和巨噬细胞htr3对主动脉外膜的影响可能是由于缺乏解剖结构所致。 障碍。此外，我们假设腹主动脉周围脂肪衍生的5-羟色胺产生的区域差异，其 Angii的调控及其刺激巨噬细胞Htr3的能力导致了Angii的地区差异。 诱发的大动脉病变。目标1将确定地区差异对5-羟色胺及其受体合成的影响 血管紧张素Ⅱ对血管紧张素Ⅱ诱导的大鼠腹主动脉周围脂肪局部发育的调节作用 大动脉病变。目的2将明确巨噬细胞Htr3在血管紧张素Ⅱ诱导的区域发展中的机制 主动脉病变及5-羟色胺/Htr3促进巨噬细胞炎症和线粒体机制的研究 功能障碍。这些研究的结果将通过5-羟色胺/htr3确定主动脉周围脂肪的新作用。 机制，关于区域性大动脉病变的发展，并可能确定优化的新治疗靶点 特定的区域性大动脉病变。