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Global Translational Medicine Metabolic dysfunction in vascular senescence

senescent cells; p21 is a downstream cell cycle-dependent Lipopolysaccharides can upregulate the expression of
kinase (CDK) of phosphorylated p53 and functions as a bromodomain-containing protein 4, which is involved in
cell cycle inhibitor by binding to and inhibiting CDK2, inflammation-induced macrophage senescence, through
preventing the transition from the G1 to the S phase of nuclear factor kappa B (NF-κB) pathway activation.
the cell cycle. For example, young mice with defective Senescent macrophages are characterized by morphological
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endothelial DNA repair exhibit elevated p21 expression in changes, SASP, DNA damage response, and promotion of
their endothelial cells, thereby developing atherosclerosis. 11 lipid uptake associated with atherosclerosis. Reportedly,
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extracellular signal-regulated kinase 5 (ERK5) promotes
2.2.2. Smooth muscle cell senescence atherosclerotic plaque formation and senescence-
Vascular smooth muscle cells (VSMCs) exhibit remarkable associated phenotype secretions via aryl hydrocarbon
plasticity and undergo phenotypic transformation owing receptor signaling in macrophages, particularly in the
to various pathological stimuli, such as proinflammatory ERK5 S496A KI mouse model. Moreover, at the onset of
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cytokines and mechanical stretch. VSMC senescence atherosclerosis, senescent foamy macrophages accumulate
promotes atherosclerosis and arterial calcification, leading in the endothelium, inducing an atherosclerotic process
to decreased arterial compliance and impaired elastic with increased levels of inflammatory cytokines (e.g.,
reservoir function, which serves as the pathological basis IL-1α and TNF-α), chemokines, and metalloproteinase
of diseases, such as hypertension, and represents an (e.g., Mmp3 and Mmp13). However, in advanced lesions,
independent risk factor for heart failure. 15 senescent cells contribute to plaque destabilization by
enhancing metalloproteinase production, including elastic
VSMCs’ phenotypic transformation plays a crucial 21
role in vascular senescence. Cellular senescence fiber degradation and fibrous cap thickness reduction.
These findings suggest that macrophage senescence
promotes the transformation of VSMCs to SASP, and this promotes atherosclerosis development and maturation. In
phenotypic transition enhances the synergistic effects,
accelerating arterial senescence. A study on mouse addition to other senescent cells, endothelial cells (marked
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Ink4a+
models of senescence and hypertension demonstrated by p16 ), and VSMCs, senescent macrophages drive
that levels of contractile markers (e.g., α-SM-actin and atherosclerotic plaque formation and create a conducive
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calponin) decreased and those of synthetic markers (e.g., environment for further growth of lesions.
osteopontin) increased in both models. Furthermore, 2.2.4. Stem cell senescence
this effect was pronounced in the senescence and
hypertension combination, accompanied by a decrease Stem cells possess the capacity for self-renewal and
and an increase in protein kinase B and mitogen-activated multilineage differentiation. Under normal conditions,
protein kinase signaling, respectively, indicating reciprocal adult stem cells exist in a quiescent state in many tissues.
regulation of VSMC phenotypic switching. However, the However, alterations in the tissue microenvironment activate
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phenotypic switch of VSMCs offers novel insights into the these cells, which is essential for tissue homeostasis.
development of aneurysms. A recent study demonstrated When stem cells become senescent, the organism
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that age-related nuclear factor (erythroid-derived 2)-like 2 experiences a reduction of cells capable of participating
(NRF2) dysfunction acts as a contributing factor to VSMC in the renewal processes, resulting in senescence when
senescence and VC in VSMC-specific Nrf2-knockdown homeostasis is disrupted. Therefore, stem cell senescence
mice. In addition, repressors of DNA-binding 2 (Id2) – a is considered a crucial characteristic and driving force
core downstream gene regulated by NRF2, along with of organismal senescence and various senescence-
Id2 overexpression – can alleviate VC induced by NRF2 related diseases. A comprehensive understanding of the
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silencing-induced VC and VSMC senescence. These mechanisms underlying stem cell senescence can identify
findings highlight the protective role played by the NRF strategies for preserving and promoting the regenerative
2–ID2 axis against calcification by counteracting VSMC capacity of stem cells to maintain tissue function during
senescence. 18 senescence. Multiple molecular mechanisms are involved
in stem cell senescence, with key doctrines including
2.2.3. Macrophage senescence (1). oxidative stress damage: excessive ROS accumulation
Macrophages are immune cells that primarily respond induces oxidative stress and cellular senescence –
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to immune challenges through phagocytosis, removing a hallmark of senescent stem cells. In stem cells,
damaged cells and cellular debris. In contrast, macrophage oxidative stress damages proteins, lipids, and DNA
senescence is characterized by persistent cell cycle arrest and activates senescence-associated genes, such as
and a secretory phenotype associated with chronic, low- p53 and p16 INK4a , inducing stem cells into a senescent
grade inflammation-like senescence. state 26

Volume 3 Issue 4 (2024) 4 doi: 10.36922/gtm.4619