The serotonergic system in periaortic fat regulates regional aortopathy development

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.

Grant Number: 5R01HL168633-03
NIH Institute/Center: NIH
Principal Investigator: Lisa Cassis