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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.

主动脉病变是一种危险的血管疾病，目前尚无治疗方法，可发生在不同的主动脉区域