Perivascular adipose tissue modulates aortic reactivity in Marfan syndrome mice in a sex- and region-specific manner: Redox-dependent anticontractile effects in the female ascending aorta

Abstract

Marfan syndrome (MFS), caused by fibrillin-1 (FBN1) mutations, leads to thoracic aortic aneurysm formation through mechanisms in which redox imbalance plays an important role. Perivascular adipose tissue (PVAT) modulates vascular tone, but its role in aortic reactivity in MFS is unknown. To address this, we examined thoracic aortic reactivity using wire myography in ascending and descending aortic segments from 2 to 3-month-old male and female wild-type and Fbn1C1041G/+ mice with or without PVAT. PVAT-mediated modulation of α1-adrenergic phenylephrine-induced contractions was preserved in the ascending aorta of male MFS mice. In contrast, in the descending thoracic aorta, PVAT from MFS mice exerted an anticontractile effect irrespective of sex. In the female ascending aorta, PVAT induced a genotype-dependent attenuation of contractile responses that persisted after endothelial denudation but was lost with aging. Despite comparable nitric oxide synthase (NOS) expression and NO levels, pharmacological NOS inhibition with L-NAME or selective inducible NOS blockade with 1400 W abolished the PVAT-induced anticontractile effect. Molecular, histological, and synchrotron radiation-based Fourier-transform infrared microspectroscopy analyses showed increased Nox4 expression and oxidative-nitrosative stress in MFS PVAT, without evidence of lipid oxidation or changes in protein secondary structure. Catalase (an H2O2 scavenger) or FeTPPS (a peroxynitrite decomposition catalyst) abolished the PVAT-dependent attenuation of contractility, supporting an integrated redox signaling mechanism. These findings identify PVAT as a sex- and region-specific modulator of aortic reactivity in MFS. In female mice, PVAT-dependent attenuation of α1-adrenergic contractility involves redox-sensitive pathways, highlighting PVAT-derived reactive oxygen/nitrogen species signaling as a potential therapeutic target in MFS-associated aortopathy.