Researchers publishing in Aging Cell have discovered that the nuclei of the cells that line injured arteries quickly become misshapen and that this leads to accelerated cellular senescence. Delivering zinc to these cells partially alleviates this dysmorphism.
Two seemingly unrelated concepts
This paper begins with a discussion of two different concepts that, on the surface, appear to be unrelated. First, the researchers discuss vascular damage, particularly in the context of surgeries; even minimally invasive procedures that involve cutting, scraping, or burning arteries must cause some level of damage. This includes such procedures as catheter implantation as a treatment for heart disease [1] and the resection of cancerous tumors [2].
The paper then pivots towards the shapes of the nuclei within cells. Misshapen nuclei are a biomarker of cellular senescence [3]. Dysfunction of the lamina, which maintains the nucleus’ shape, is linked to DNA damage [4]. Mutations of the Lamin A gene are well-known to be key in accelerated aging (progeria), and the accumulation of its immature and nonfunctional precursor, prelamin A, has been linked to vascular aging [5].
This work bridges those two concepts, demonstrating that vascular aging is directly linked to physical injury.
The muscle cells of injured arteries have misshapen nuclei
The researchers first examined the arteries of 18 human donors. Some of them had underwent percutaneous transluminal angioplasty (PTA), a procedure that damages the femoral arteries by necessity, before later having their femoral arteries removed for unrelated reasons. A control group had their femoral arteries removed without ever receiving PTA.
The nuclei of the vascular smooth muscle cells (VSMCs) in the control group’s arteries were cigar-shaped, but the nuclei of the VSMCs in the PTA group’s arteries were visibly dysmorphic, with inconsistent shapes and common irregularities. A similar experiment that involved using balloons to damage the carotid arteries of rats yielded similar results; the nuclei of the rats’ VSMCs in the area became significantly misshapen. This altered morphology was found to occur immediately after injury.
This altered morphology was directly linked to aging. In the human samples, injured arteries were found to be more likely to express the senescence biomarker SA-β-gal, while in rat samples, SA-β-gal was directly linked to a loss of nuclear solidity, demonstrating that these injuries lead to cellular senescence.
These researchers had previously found that the release of platelet-derived microvesicles (pMVs) after injuries leads to vascular dysfunction [6]. Here, the researchers demonstrated that administering pMVs directly to vascular tissues leads to the nuclear dysmorphism found in naturally injured arteries. This was found to be due to an accumulation of prelamin A; cells with more accumulation of prelamin A were found to be more dysmorphic.
Similarly, using CRISPR to modify cells into not being able to properly process prelamin A, by depriving them of the enzyme Zmpste24, led to the same dysmorphism. As expected, mice that were engineered not to produce this key enzyme experienced accelerated vascular aging.
Zinc is the key
The mineral zinc is a key part of the function of Zmpste24, and administering zinc alongside pMVs was found to nearly negate their negative effects. On the other hand, administering TPEN, which chelates zinc away from cells, was found to cause similar nuclear dysmorphism as pMVs. Experimenting with Zmpste24-deficient cells determined that this enzyme was indeed responsible for preventing the dysmorphism.
In injured VSMCs, there is a downregulation of ZIP4, a protein responsible for bringing zinc into these cells. These effects were also recapitulated with the direct administration of pMVs.
The researchers then performed another experiment on rats. In addition to a control group, some of the rats were fed a zinc-rich diet, while others were given ZIF-8, a nanoparticle that encloses zinc within platelet membranes. These rats were then subjected to vascular injury. The rats fed a high-zinc diet were found to express slightly less prelamin A, and the ZIF-8-treated rats were found to express even less, although the injury’s effects were not completely mitigated. A further examination of the treated rats did not find any side effects caused by ZIF-8.
The researchers report that their “findings reveal that the pMVs/ZIP4/zinc/prelamin A axis constitutes a novel signaling pathway regulating nuclear dysmorphism and vascular aging.” If these findings can be corroborated, it is reasonable to suggest that zinc supplementation, or the use of ZIF-8 nanoparticles, should be included as part of the surgical process in order to prevent accelerated aging of the associated vasculature.
Literature
[1] Calabro, P., Gragnano, F., Niccoli, G., Marcucci, R., Zimarino, M., Spaccarotella, C., … & Working Group of Interventional Cardiology and the Working Group of Thrombosis of the Italian Society of Cardiology. (2021). Antithrombotic therapy in patients undergoing transcatheter interventions for structural heart disease. Circulation, 144(16), 1323-1343.
[2] Eom, B. W., Yoon, H. M., Kim, Y. W., Min, J. S., An, J. Y., Hur, H., … & Ryu, K. W. (2024). Quality of life and nutritional outcomes of stomach-preserving surgery for early gastric cancer: a secondary analysis of the SENORITA randomized clinical trial. JAMA surgery, 159(8), 900-908.
[3] Heckenbach, I., Mkrtchyan, G. V., Ezra, M. B., Bakula, D., Madsen, J. S., Nielsen, M. H., … & Scheibye-Knudsen, M. (2022). Nuclear morphology is a deep learning biomarker of cellular senescence. Nature Aging, 2(8), 742-755.
[4] Pérez-Hernández, M., van Opbergen, C. J., Bagwan, N., Vissing, C. R., Marrón-Liñares, G. M., Zhang, M., … & Lundby, A. (2022). Loss of nuclear envelope integrity and increased oxidant production cause DNA damage in adult hearts deficient in PKP2: a molecular substrate of ARVC. Circulation, 146(11), 851-867.
[5] Revêchon, G., Witasp, A., Viceconte, N., Helgadottir, H. T., Machtel, P., Stefani, F., … & Eriksson, M. (2025). Recurrent somatic mutation and progerin expression in early vascular aging of chronic kidney disease. Nature Aging, 5(6), 1046-1062.
[6] Bao, H., Li, Z. T., Xu, L. H., Su, T. Y., Han, Y., Bao, M., … & Qi, Y. X. (2021). Platelet-derived extracellular vesicles increase Col8a1 secretion and vascular stiffness in intimal injury. Frontiers in cell and developmental biology, 9, 641763.
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