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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

基本信息

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
项目类别：
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

项目摘要

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.

主动脉病变是危险的血管疾病，没有已知的治疗方法，可以发生在不同的主动脉区域取决于遗传和环境因素。围绕主动脉不同区域的主动脉周围脂肪是由不同的脂肪细胞和神经元成分组成，并已报道与人类脊椎病初步数据表明，主动脉周围脂肪中的5-羟色胺（5-HT）水平因主动脉类似地，5-HT 3受体（Htr 3）沿着主动脉长度存在差异表达。血管紧张素II（AngII）是一种众所周知的局部血管病变刺激物，调节胸主动脉周围棕色脂肪中的5-HT水平，但不调节腹主动脉周围白色脂肪，AngII促进从具有粘附的主动脉周围脂肪的胸主动脉切片中神经元释放5 HT。此外，J774 巨噬细胞对5 HT的反应促进炎症，并通过 Htr 3介导的机制。值得注意的是，给予AngII输注小鼠Htr 3拮抗剂，区域性脊髓炎。我们假设主动脉周围脂肪来源的5-HT作用于Htr 3，主动脉周围脂肪内的巨噬细胞促进主动脉外膜炎症并刺激线粒体活性氧产生，导致AngII诱导的前列腺病变。动脉周围脂肪的能力- 衍生的5 HT和巨噬细胞Htr 3影响主动脉外膜可能是由于缺乏解剖结构屏障此外，我们假设，在主动脉周围脂肪来源的5-HT产生的区域差异， AngII的调节及其刺激巨噬细胞Htr 3的能力有助于AngII的区域差异。诱发性脊髓炎。目标1将定义区域差异对5-HT合成及其血管紧张素II在主动脉周围脂肪中对血管紧张素II诱导的局部发展和进展的调节脊椎病目的2：探讨巨噬细胞Htr 3在AngII诱导的血管紧张素Ⅱ局部病变中的作用机制。研究5 HT/Htr 3促进巨噬细胞炎症和线粒体损伤的机制功能障碍这些研究的结果将通过5 HT/Htr 3的表达，确定主动脉周围脂肪的新作用。机制，对区域性脊椎病的发展，并可能确定新的治疗目标优化，特定区域性主动脉病变。