Hildebrand, S.; Wunderling, K.; Siwik-Rog, Z.; Schmidt, A.; Barrero, J. A.; Gomez-Banoy, N.; Reverte-Salisa, L.; Freyter, B.; Zimmer, S.; Nickenig, G.; Cohen, P.; Pfeifer, A.

Aim: Aortic stenosis (AS) is a common condition with exponential increases in incidence in aging populations. Perivascular adipose tissue (PVAT) forms the outer layer of the aortic wall and has - especially in the thoracic area - characteristics of thermogenic adipose tissue, which dissipates energy and releases endocrine factors. Here, we set out to investigate the role of thermogenic PVAT in AS. Methods and results: We studied the role of (PVAT) in the development of AS in a murine model of AS. To specifically delineate the role of PVAT activity in AS, we used a pharmacological {beta}3-adrenergic agonist as well as cold exposure in combination with a genetic mouse model with deficient PVAT development. To investigate the role of thermogenic adipose tissue in human AS, we used 18F-FDG PET-CT imaging. We found that pharmacological activation of thermogenic adipose tissue resulted in an improvement of AS, but not in mice genetically deficient in PVAT. Similarly, PVAT was found to be protective against AS during physiological stimulation of PVAT using cold exposure. Mechanistically, PVAT activation resulted in enhanced aortic distensibility and cellular remodeling of the aortic wall, possibly via release of polyunsaturated fatty acids and oxylipins from perivascular adipocytes. Finally, analysis of thermogenic fat activity in humans revealed that mediastinal thermogenic fat activity correlated negatively with diagnostic criteria of AS severity, suggesting an important role for PVAT activity in human AS. Conclusion: Our data indicate that PVAT activation reduces aortic stenosis and supports aortic remodeling to improve ascending aorta hemodynamics. PVAT activation might be a novel therapeutic target to ameliorate AS progression. Translational perspective: Currently, there are no effective strategies for treating AS other than valve replacement. Since the molecular mechanisms underlying the disease progression remain unclear, there are no pharmacological agents approved for either treatment or prevention of this disease. Furthermore, AS development cannot currently be predicted and is often only diagnosed when patients develop symptoms, which may be 10-20 years after disease onset. Therefore, identifying novel mechanisms that improve aortic valve function and prevent AS is of high medical need. This study identifies activation of PVAT-dependent aortic remodeling as a potential new therapeutic approach to improve or prevent AS.