Open AccessSenescent cells suppress innate smooth muscle cell repair functions in atherosclerosis
Author(s) -
Bennett G. Childs,
Cheng Zhang,
Fahad Shuja,
Ines Sturmlechner,
Shawn Trewartha,
Raul O. Fierro Velasco,
Darren J. Baker,
Hu Li,
Jan M. van Deursen
Publication year - 2021
Publication title -
nature aging
Language(s) - English
Resource type - Journals
ISSN - 2662-8465
DOI - 10.1038/s43587-021-00089-5
Subject(s) - elastin , vascular smooth muscle , lesion , genetically modified mouse , cancer research , microbiology and biotechnology , transgene , medicine , chemistry , smooth muscle , pathology , biology , biochemistry , gene
Senescent cells (SNCs) degenerate the fibrous cap that normally prevents atherogenic plaque rupture, a leading cause of myocardial infarction and stroke. Here we explored the underlying mechanism using pharmacological or transgenic approaches to clear SNCs in the Ldlr -/- mouse model of atherosclerosis. SNC clearance reinforced fully deteriorated fibrous caps in highly advanced lesions, as evidenced by restored vascular smooth muscle cell (VSMC) numbers, elastin content, and overall cap thickness. We found that SNCs inhibit VSMC promigratory phenotype switching in the first interfiber space of the arterial wall directly beneath atherosclerotic plaque, thereby limiting lesion entry of medial VSMCs for fibrous cap assembly or reinforcement. SNCs do so by antagonizing IGF-1 through the secretion of insulin-like growth factor-binding protein 3 (Igfbp3). These data indicate that the intermittent use of senolytic agents or IGFBP-3 inhibition in combination with lipid lowering drugs may provide therapeutic benefit in atherosclerosis.