Preoperative methionine restriction induces perivascular adipose tissue browning and improves vein graft remodeling in male mice

Peter Kip, Thijs J. Sluiter, Michael R. MacArthur, Ming Tao, Nicky Kruit, Sarah J. Mitchell, Jonathan Jung, Sander Kooijman, Josh Gorham, Jonathan G. Seidman, Paul H. A. Quax, Julius L. Decano, Masanori Aikawa, C. Keith Ozaki, James R. Mitchell and Margreet R. Vries ()
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Peter Kip: Harvard Medical School
Thijs J. Sluiter: Harvard Medical School
Michael R. MacArthur: Harvard T.H. Chan School of Public Health
Ming Tao: Harvard Medical School
Nicky Kruit: Leiden University Medical Center
Sarah J. Mitchell: Princeton University
Jonathan Jung: Harvard T.H. Chan School of Public Health
Sander Kooijman: Leiden University Medical Center
Josh Gorham: Harvard Medical School
Jonathan G. Seidman: Harvard Medical School
Paul H. A. Quax: Leiden University Medical Center
Julius L. Decano: Harvard Medical School
Masanori Aikawa: Harvard Medical School
C. Keith Ozaki: Harvard Medical School
James R. Mitchell: Harvard T.H. Chan School of Public Health
Margreet R. Vries: Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Short-term preoperative methionine restriction (MetR) is a promising translatable strategy to mitigate surgical injury response. However, its application to improve post-interventional vascular remodeling remains underexplored. Here we find that MetR protects from arterial intimal hyperplasia in a focal stenosis model and pathologic vascular remodeling following vein graft surgery in male mice. RNA sequencing reveals that MetR enhances browning in arterial (thoracic aorta) perivascular adipose tissue (PVAT) and induces it in venous (caval vein) PVAT. Specifically, Ppara is highly upregulated in PVAT-adipocytes upon MetR. Furthermore, MetR dampens the postoperative pro-inflammatory response to surgery in PVAT-macrophages in vivo and in vitro. This study shows that the detrimental effects of dysfunctional PVAT on vascular remodeling can be reversed by MetR, and identifies pathways involved in MetR-induced browning of PVAT. Furthermore, we demonstrate the potential of short-term preoperative MetR as a simple intervention to ameliorate vascular remodeling after vascular surgery.

Date: 2024
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DOI: 10.1038/s41467-024-53844-8

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