Perivascular adipose tissue dysfunction contributes to thoracic aortic aneurysm development.

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 naturally surrounded by perivascular adipose tissue (PVAT), which produces and releases adipokines and other factors in a paracrine manner that are pivotal for vascular physiology and pathophysiology. Under healthy conditions, thoracic PVAT resembles brown adipose tissue (BAT) and maintains vascular homeostasis. In response to pathogenic stimuli, PVAT can undergo whitening and become dysfunctional, contributing to the development of vascular diseases. However, a causal relationship between PVAT dysfunction and TAA pathogenesis, as well as the underlying mechanisms, remain unknown. This study investigated the roles of PPARg (a key determinant of adipogenesis) and PRDM16 (a key determinant of brown adipocyte development) in PVAT on TAA development.

Methods: PVAT samples from TAA patients were collected and evaluated. Mice lacking PVAT and those with dysfunctional PVAT were generated by crossbreeding Ucp1 promoter-driven Cre mice with Pparg floxed mice (brown adipocyte-specific Pparg knockout, Pparg^BAKO) and Prdm16 floxed mice (brown adipocyte-specific Prdm16 knockout, Prdm16^BAKO), respectively. TAA formation was induced by perivascular application of porcine pancreatic elastase (PPE) and evaluated through histological staining. Luciferase reporter assays and chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) were used to determine PRDM16 target genes.

Results: We found that PVAT near TAA lesions in patients exhibited reduced expression of browning markers and increased expression of whitening markers. Pparg^BAKO mice showed impaired PVAT development, while Prdm16^BAKO mice displayed a loss of browning in PVAT. Both Pparg^BAKO and Prdm16^BAKO mice exhibited aggravated TAA formation. We identified decorin, a small proteoglycan of the extracellular matrix, as a transcriptional repressive target gene of PRDM16. The expression of decorin was increased in dysfunctional PVAT and the plasma of TAA patients.

Conclusions: The development and maintenance of brown-like characteristics in PVAT are necessary to protect against TAA formation. PVAT dysfunction contributes to TAA development. Our study provides a promising therapeutic strategy for preventing TAA progression by inducing PVAT browning.