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.

We will define mechanisms for regional formation of aneurysms in the aorta, a deadly disease with no therapies. We will focus on a neurotransmitter produced by fat surrounding the aorta. This novel target may provide a therapeutic target for aneurysmal disease.