β-Adrenergic Stimulation-Induced PVAT Dysfunction in Male Sex: A Role for 11β-Hydroxysteroid Dehydrogenase-1

Abstract

Abstract Long-term β-adrenoceptor (β-AR) stimulation is a pathological mechanism associated with cardiovascular diseases resulting in endothelial and perivascular adipose tissue (PVAT) dysfunction. In this study, we aimed to identify whether β-adrenergic signaling has a direct effect on PVAT. Thoracic aorta PVAT was obtained from male Wistar rats and cultured ex vivo with the β-AR agonist isoproterenol (Iso; 1 µM) or vehicle for 24 hours. Conditioned culture medium (CCM) from Iso-treated PVAT induced a marked increase in aorta contractile response, induced oxidative stress, and reduced nitric oxide production in PVAT compared to vehicle. In addition, Iso-treated PVAT and PVAT-derived differentiated adipocytes exhibited higher corticosterone release and protein expression of 11β–hydroxysteroid dehydrogenase type 1 (11β-HSD1), an enzyme responsible for de novo synthesis of corticosterone. Macrophages exposed to Iso also exhibited increased corticosterone release in response to β-AR stimulation. Incubation of Iso-treated PVAT and PVAT-derived differentiated adipocytes with β3-AR antagonist restored aorta contractile function modulated by Iso-CCM and normalized 11β-HSD1 protein expression. These results show that β3-AR signaling leads to upregulation of 11β-HSD1 in PVAT, thus increasing corticosterone release and contributing to impair the anticontractile function of this tissue.