A Senescence-Related Target for Blood Vessel Formation

In an article published in Aging Cell, researchers uncover a significant target that could enhance the treatment of arterial clogs, a pressing health issue for millions.

Understanding the Role of Macrophages in Blood Vessel Formation

Heart attacks and strokes are not the only issues linked to clogged blood vessels; peripheral arterial disease (PAD) emerges when these blockages occur in the extremities, affecting approximately 113 million individuals globally [1]. Although some instances can be remedied through surgical intervention, such procedures become increasingly complex in older populations [2]. Hence, the ideal approach would be to stimulate the body’s natural ability to repair these blood vessels [3], a method that has faced challenges due to the aging process [4].

The Senescent Macrophages Dilemma

Previous studies have illuminated the reasons behind these challenges. While normally, macrophages facilitate the formation of new blood vessels through a process called angiogenesis [5], they eventually undergo senescence [6], resulting in various downstream disorders. For instance, PAD is marked by alterations in vascular endothelial growth factor A (VEGF-A), notably a decrease in the isoform VEGF-A165A paired with an increase in VEGF-A165B [7]. Intrigued by macrophages' role in this shift, researchers sought to evaluate whether macrophage senescence was the underlying cause.

Experimental Findings

The study began with a thorough analysis of macrophage senescence. Expectantly, results indicated that macrophages from the skeletal muscle of older mice demonstrated decreased proliferative capabilities, elevated levels of inflammatory factors, and increased senescence biomarkers such as p16, p21, and SA-β-gal.

Subsequently, these senescent macrophages were injected into young mice following a hindlimb injury. Notably, the control group and those receiving non-senescent macrophages exhibited no significant differences in angiogenesis. However, the young mice receiving senescent macrophages mimicked older mice under similar conditions: they presented a heightened risk of necrosis in the toes, increased muscle fibrosis, and diminished capillary presence during recovery. Moreover, even an existing artery unrelated to the injury exhibited a reduced diameter due to the influence of senescent macrophages.

This adverse effect extended to the endothelial cells—the cells that comprise the blood vessel linings. Their proliferation capability was hindered, and a vital pathway necessary for angiogenesis was compromised.

Mechanistic Insights

As anticipated, these detrimental changes were directly linked to VEGF-A165B. In one experimental group, researchers inhibited the gene responsible for producing this protein, while in another group, they introduced an antibody against it. Both strategies successfully prevented the harmful effects of senescent macrophages on endothelial cell functions.

Subsequent experiments administering senescent macrophages modified to abstain from VEGF-A165B production yielded angiogenesis and tissue necrosis results comparable to those seen with non-senescent macrophages. Interestingly, delivering non-senescent macrophages incapable of producing VEGF-A165B also yielded positive outcomes.

Implications for Future Research

When examining human participants, older individuals presented with elevated levels of both total VEGF-A and specifically VEGF-A165B. This elevation correlates significantly with reduced blood vessel sizes. Despite the promising findings, the authors acknowledge certain limitations, including the inability to categorize results based on sex, an essential factor in PAD susceptibility [8].

Nevertheless, these findings illuminate the potential of targeting senescent macrophages with senolytics or developing anti-VEGF-A165B therapies for treating PAD.

Literature Cited

# Reference
1 Kim, M. S., et al. (2023). Global burden of peripheral artery disease and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. The Lancet Global Health, 11(10), e1553-e1565.
2 Gornik, H. L., et al. (2024). 2024 ACC/AHA Guidelines for the management of lower extremity peripheral artery disease. Journal of the American College of Cardiology, 83(24), 2497-2604.
3 Annex, B. H., & Cooke, J. P. (2021). New directions in therapeutic angiogenesis in peripheral arterial disease. Circulation Research, 128(12), 1944-1957.
4 Cooke, J. P., & Losordo, D. W. (2015). Modulating the vascular response to limb ischemia. Circulation Research, 116(9), 1561-1578.
5 Takeda, Y., et al. (2011). Macrophage skewing prevents ischemia by inducing arteriogenesis. Nature, 479(7371), 122-126.
6 Lin, J. B., et al. (2018). Oxysterol signatures distinguish age-related macular degeneration. EBioMedicine, 32, 9-20.
7 Kikuchi, R., et al. (2014). An antiangiogenic isoform of VEGF-A contributes to impaired vascularization in PAD. Nature Medicine, 20(12), 1464-1471.
8 Pabon, M., et al. (2022). Sex differences in peripheral artery disease. Circulation Research, 130(4), 496-511.

In conclusion, this research highlights the intricate relationship between macrophage senescence, VEGF-A isoforms, and blood vessel formation. Targeting these processes may represent a promising avenue for improving treatment strategies for PAD and related vascular diseases.

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