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Senescent Macrophages Promote Age-Related Revascularization Impairment by Increasing Antiangiogenic VEGF-A165B
Minghong Chen1,2,3, Junyu Chen1,2,3, Yu Liu3,4
1Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Abstract:
Peripheral arterial disease is a common vascular disease in the elderly. Therapeutic revascularization, including angiogenic and arteriogenic therapy, is a promising treatment approach for peripheral arterial disease. However, the progress of clinical trials is not ideal, possibly due to insufficiency of preclinical models, such as not taking into account the effect of aging on vascular regeneration. Macrophages are crucial in angiogenesis and arteriogenesis. The aging microenvironment typically makes recruited monocytes and macrophages more susceptible to senescence. However, the feature of macrophages in ischemic hindlimb muscle of old individuals and their underlying role remains unclear. In this study, we reveal that macrophages of ischemic skeletal muscle in old mice are more senescent and proinflammatory. By transplanting macrophages into mice following hindlimb ischemia, we find senescent macrophages inhibit revascularization. Mechanistically, these senescent macrophages induce endothelial dysfunction via increasing vascular endothelial growth factor A-165B (VEGF-A165B) expression and secretion, and eventually impair revascularization. Notably, plasma VEGF-A165B levels are elevated in old patients with PAD and positively associated with a lower ankle brachial index (ABI). Our study suggests that targeting the senescent macrophages presents an avenue to improve age-related revascularization damage.
Insights
Senescent macrophages in aging hinder vascular repair after limb ischemia by promoting inflammation and endothelial dysfunction. Targeting these senescent cells may improve blood vessel regeneration in older patients with peripheral arterial disease.
Area of Science:
- Vascular Biology
- Aging Research
- Immunology
Background:
- Peripheral arterial disease (PAD) is prevalent in the elderly, with limited success in clinical revascularization trials.
- Aging affects immune cells, potentially impairing vascular regeneration, but the role of aged macrophages in ischemic tissues is unknown.
Purpose of the Study:
- To investigate the characteristics and function of macrophages in the ischemic hindlimb muscle of aged mice.
- To determine the impact of senescent macrophages on vascular regeneration and identify underlying mechanisms.
Main Methods:
- Analysis of macrophages in ischemic hindlimb muscle of aged mice.
- Macrophage transplantation experiments in mice with hindlimb ischemia.
- Assessment of endothelial function and vascular endothelial growth factor A-165B (VEGF-A165B) levels.
- Correlation analysis with patient data (PAD patients, ankle-brachial index).
Main Results:
- Macrophages in ischemic muscle of aged mice exhibit senescence and a proinflammatory phenotype.
- Transplanted senescent macrophages significantly inhibit revascularization in a mouse model.
- Senescent macrophages impair endothelial function by increasing VEGF-A165B expression and secretion.
- Elevated plasma VEGF-A165B levels and lower ankle-brachial index (ABI) were observed in elderly PAD patients.
Conclusions:
- Senescent macrophages contribute to impaired vascular regeneration in aging.
- VEGF-A165B mediated by senescent macrophages is a key factor in endothelial dysfunction and reduced revascularization.
- Targeting senescent macrophages offers a potential therapeutic strategy for age-related vascular complications in PAD.
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