Senescent Macrophages Inhibit Vascularization in Aged Individuals
Why does the ability to generate new blood vessels decline with age? One manifestation is a loss of capillaries, which become less dense in tissues with age. Another issue is that efforts to produce therapies that provoke the growth of new vessels, as a way to treat conditions such as peripheral artery disease results from reduced blood flow through vessels obstructed by atherosclerotic plaque, have struggled due to this age-related impairment of blood vessel growth processes. Here, researchers provide evidence for senescent macrophage cells to be an important contributing cause of dysfunction in blood vessel growth and maintenance in older people. This is yet another reason to push for more clinical trials and greater use of existing low-cost senolytic treatments such as the dasatinib and quercetin combination.
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 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. Due to the presence of two splicing isoforms, the role of VEGF-A in revascularization is complex: VEGF-A165A is the the proangiogenic isoform, while VEGF-A165B is the antiangiogenic isoform. Notably, plasma VEGF-A165B levels are elevated in old patients with peripheral arterial disease and positively associated with a lower ankle brachial index, an assessment of disease severity. Our study suggests that targeting the senescent macrophages presents an avenue to improve age-related revascularization damage.