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Follistatin Alleviates Vascular Dysfunction by Reducing Oxidative Stress and Promoting Browning in Perivascular
Ann Kuganathan1, Chao Lu1, Melissa MacDonald1
1Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Canada (A. Kuganathan, C.L., M.M.D., B.G., J.D., J.C.K.).
Background:
Essential hypertension, characterized by vascular dysfunction, remains a leading modifiable cause of death globally. Perivascular adipose tissue (PVAT), which normally reduces vasoconstriction, becomes contractile in hypertension due to increased reactive oxygen species (ROS). Brown PVAT has emerged as a protective regulator of vascular tone. Follistatin, an activin antagonist, induces adipose tissue browning via AMPK (AMP-activated protein kinase). We recently reported improved blood pressure and vascular function by follistatin in the spontaneously hypertensive rat (SHR) model of essential hypertension. Here, we investigate whether follistatin reduces ROS and induces browning in SHR PVAT to restore PVAT-mediated vascular function.
Methods:
SHRs were treated with vehicle, follistatin, or hydralazine for 8 weeks. Mesenteric white and thoracic brown PVAT from SHR and normotensive Wistar-Kyoto mice were used, with wire myography used to assess vascular function. PVAT nitric oxide, ROS, and browning markers were assessed via immunohistochemistry. PVAT was treated ex vivo to assess mechanisms of browning. Unbiased proteomic analysis of PVAT was performed using liquid chromatography-mass spectrometry.
Results:
SHR PVAT dysfunction, manifesting as a procontractile effect, was inhibited by follistatin through reducing ROS, enhancing NO bioavailability, and promoting browning. These effects were mediated by activin neutralization and AMPK phosphorylation. Hydralazine-induced blood pressure reduction did not replicate follistatin effects, suggesting vascular benefits of follistatin are mediated by direct PVAT modulation. Proteomic analysis revealed a shift in proteome towards a normal state, upregulating processes associated with adipose browning.
Conclusions:
Follistatin restores PVAT-mediated vascular relaxation via ROS reduction, activin neutralization, and AMPK-dependent browning, positioning the potential for PVAT as a therapeutic target for vascular dysfunction in essential hypertension.
