2. Academic Validation
  3. Increased vascular smooth muscle cell senescence in aneurysmal Fibulin-4 mutant mice

Increased vascular smooth muscle cell senescence in aneurysmal Fibulin-4 mutant mice

  • NPJ Aging. 2024 Jun 20;10(1):31. doi: 10.1038/s41514-024-00154-4.
Sanne J M Stefens 1,  Nicole van Vliet 1,  Arne IJpma 2,  Joyce Burger 1 3,  Yunlei Li 2,  Paula M van Heijningen 1,  Jan H N Lindeman 4,  Danielle Majoor-Krakauer 3,  Hence J M Verhagen 5,  Roland Kanaar 1 6 7,  Jeroen Essers 8 9 10,  Ingrid van der Pluijm 11 12
Affiliations

Affiliations

  • 1 Department of Molecular Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • 2 Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • 3 Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • 4 Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands.
  • 5 Department of Vascular Surgery, Cardiovascular Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • 6 Department of Radiotherapy, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • 7 Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands.
  • 8 Department of Molecular Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands. j.essers@erasmusmc.nl.
  • 9 Department of Vascular Surgery, Cardiovascular Institute, Erasmus University Medical Center, Rotterdam, The Netherlands. j.essers@erasmusmc.nl.
  • 10 Department of Radiotherapy, Erasmus University Medical Center, Rotterdam, The Netherlands. j.essers@erasmusmc.nl.
  • 11 Department of Molecular Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands. i.vanderpluijm@erasmusmc.nl.
  • 12 Department of Vascular Surgery, Cardiovascular Institute, Erasmus University Medical Center, Rotterdam, The Netherlands. i.vanderpluijm@erasmusmc.nl.
PMID: 38902222 DOI: 10.1038/s41514-024-00154-4
Abstract

Aortic aneurysms are dilatations of the aorta that can rupture when left untreated. We used the aneurysmal Fibulin-4R/R mouse model to further unravel the underlying mechanisms of aneurysm formation. RNA Sequencing of 3-month-old Fibulin-4R/R aortas revealed significant upregulation of senescence-associated secretory phenotype (SASP) factors and key senescence factors, indicating the involvement of senescence. Analysis of aorta histology and of vascular smooth muscle cells (VSMCs) in vitro confirmed the senescent phenotype of Fibulin-4R/R VSMCs by revealing increased SA-β-gal, p21, and p16 staining, increased IL-6 secretion, increased presence of DNA damage foci and increased nuclei size. Additionally, we found that p21 luminescence was increased in the dilated aorta of Fibulin-4R/R|p21-luciferase mice. Our studies identify a cellular aging cascade in Fibulin-4 aneurysmal disease, by revealing that Fibulin-4R/R aortic VSMCs have a pronounced SASP and a senescent phenotype that may underlie aortic wall degeneration. Additionally, we demonstrated the therapeutic effect of JAK/STAT and TGF-β pathway inhibition, as well as senolytic treatment on Fibulin-4R/R VSMCs in vitro. These findings can contribute to improved therapeutic options for aneurysmal disease aimed at reducing senescent cells.

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