Short-term Pre-operative Methionine Restriction Induces Browning of Perivascular Adipose Tissue and Improves Vein Graft Remodeling in Mice

Short-term preoperative methionine restriction (MetR) shows promise as a translatable strategy to modulate the body’s response to surgical injury. Its application, however, to improve post-interventional vascular remodeling remains underexplored. Here, we find that MetR protects from arterial intimal hyperplasia in a focal stenosis model and adverse vascular remodeling after vein graft surgery. RNA sequencing reveals that MetR enhances the brown adipose tissue phenotype in arterial perivascular adipose tissue (PVAT) and induces it in venous PVAT. Specifically, PPAR-α was highly upregulated in PVAT-adipocytes. Furthermore, MetR dampens the post-operative pro-inflammatory response to surgery in PVAT-macrophages in vivo and in vitro . This study shows for the first time that the detrimental effects of dysfunctional PVAT on vascular remodeling can be reversed by MetR, and identifies pathways involved in browning of PVAT. Furthermore, we demonstrate the potential of short-term pre-operative MetR as a simple intervention to ameliorate vascular remodeling after vascular surgery. ![Figure][1] ### Competing Interest Statement The authors have declared no competing interest. * BAT : Brown Adipose Tissue BMDM : Bone Marrow-Derived Macrophages CCL2 : C-C motif ligand 2 DR : Dietary Restriction FGF21 : Fibroblast Growth Factor 21 HFD : High Fat Diet I / M : Intima / Media IH : Intimal Hyperplasia IL : Interleukin MetR : Methionine Restriction POD : Post-op Day PPAR : Peroxisome proliferator-activated receptor PVAT : Perivascular Adipose Tissue RCCA : Right Common Carotid Artery TLR4 : Toll-like receptor 4 TNF-α : Tissue necrosis factor α UCP1 : uncoupling protein 1 VSMC : Vascular Smooth Muscle Cell [1]: pending:yes