Abstract Body: Background
Thoracic aortic aneurysm (TAA) is a life-threatening disease with high morbidity and mortality rates due to fatal complications such as aortic rupture. However, molecular mechanisms underlying TAA pathogenesis remain to be fully elucidated. The aorta is uniquely surrounded by perivascular adipose tissue (PVAT), which produces and releases adipokines and other factors in a paracrine manner that are vital for vascular physiology and pathophysiology. PVAT surrounding the thoracic aorta resembles brown adipose tissue (BAT) that contributes to vascular homeostasis in health, but can undergo whitening and become dysfunctional in response to pathogenic stimuli, contributing to development of vascular diseases. PPARγ is a master regulator of PVAT development while PR-domain containing 16 (PRDM16) is a determinant of brown gene programs in PVAT and can function as a cofactor of PPARγ. PPARγ deficiency results in impaired PVAT development and PRDM16 deficiency leads to whitening of PVAT. In this study, we determined the causal relationship between PVAT dysfunction and TAA pathogenesis and explored the underlying mechanisms.
Methods and Results
We first determined that PVAT near the TAA lesion in patients was dysfunctional, showing reduced expression of browning markers. We next generated brown adipocyte-specific Pparg knockout (Pparg^BAKO) and Prdm16 knockout mice (Prdm16^BAKO) mice by crossbreeding Ucp1 promoter-driven Cre mice with Pparg floxed mice and Prdm16 floxed mice, respectively. We found that Pparg^BAKO mice showed impaired PVAT development while Prdm16^BAKO mice displayed loss of browning in PVAT, both mice exhibited aggravated TAA formation induced by perivascular application of porcine pancreatic elastase (PPE), indicating PVAT development and browning are essential for the inhibitory role of PVAT in TAA formation. By using chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) and luciferase reporter assay, we identified a PVAT-derived secretory factor known as decorin, which has been shown to promote the development of abdominal aortic aneurysm (AAA), as a direct target of PRDM16. PRDM16 significantly inhibits the expression of decorin, which subsequently functions in a paracrine manner and induces apoptosis of vascular smooth muscle cells (VAMCs), promoting TAA pathogenesis.
Conclusions
PVAT development and maintenance of the brown-like characteristics is necessary for protecting against TAA formation. PVAT dysfunction leads to TAA formation.