How our blood vessels age from the inside out

Although endotheliocytes are critically important for the functioning of blood vessels and organs, they often receive little attention in research on aging. What happens inside these cells over the years and why their function deteriorates remained a poorly understood question. This is exactly what the team of Laura de Rooy, a researcher at the CeMM Research Center (the Austrian Academy of Sciences), tried to answer.

Instead of studying the vessels as a whole, the scientists examined the activity of genes in individual endothelial cells. This approach — single‑cell analysis — allows us to see which genes are active in each cell and how this activity changes with age. By combining data from previously published single‑cell studies, the team saw an opportunity to take a closer look at these cells and detect patterns of vascular aging that would otherwise go unnoticed.

The team compiled data from 34 existing studies: more than 375,000 cells from 290 samples of 12 human tissues. By focusing on tissues classified as healthy or disease-free, the authors sought to identify molecular changes associated specifically with aging, rather than with diagnosed diseases. The result is the Human Aging Endothelial Cell Atlas, a resource that allows us to study how different populations of vascular cells change throughout the body.

A particularly interesting observation concerns the cells lining the veins. They can produce sprouts from which new vessels develop, an important part of vascular renewal. However, in older people, the activity of several genes involved in vascular formation decreased. This may explain why blood vessels lose their ability to self‑renew with age, although the study did not directly measure the ability to repair. In several tissues, researchers also recorded an increase in the activity of genes associated with inflammation and cellular senescence — a state in which cells stop dividing and can influence their environment.

“One of the most striking findings is that endothelial senescence does not look the same throughout the entire vascular system.” By combining data from different tissues, we were able to identify patterns that might have gone unnoticed when studying individual organs or types of endothelial cells separately,” the author explains.

Another discovery concerns how endothelial cells respond to their physical environment. These cells constantly perceive the forces of flowing blood and the surrounding material, converting mechanical signals into biological responses. The atlas revealed age‑related changes in the genes involved in this process.

Additional data were obtained from experiments on human skin: the YAP protein, which helps cells respond to mechanical forces, was more frequently detected inside the nuclei of endothelial cells in elderly donors. These observations raised the question: does increased YAP activity help cells cope with age‑related changes, or, conversely, does it contribute to the deterioration of vascular function?

Scientists also identified a group of genes associated with p21 — a protein capable of slowing down or stopping cell division. Comparison with endothelial cells grown in the laboratory and mouse models with accelerated aging confirmed the link to cellular aging. However, these same genes are involved in stress responses and vascular growth, so it is not yet possible to reliably distinguish permanently aging cells from cells responding to other age‑related stressors. It is necessary to understand these differences before determining which cellular processes should be targeted in future efforts to preserve vascular health.

The atlas of senescent endothelial cells provides scientists with a new resource for studying how blood vessels age in different tissues. The accompanying interactive portal will help researchers analyze molecular changes and identify promising directions for future experiments. However, the work also has limitations, as it compared people of different ages rather than tracking the same individuals over the years, and incomplete information about the donors’ lifestyles and medical histories limits the conclusions.

Nevertheless, the atlas shows that vascular aging is not uniform and is not simple. Some changes may contribute to a decline in function, while others reflect the body’s attempts to protect itself. Understanding the difference will be key to eventually learning how to help blood vessels stay healthy for longer.

“What inspires me about this atlas is that it provides a way to study vascular aging throughout the body, rather than viewing all blood vessels as aging in the same way. Now we have a resource to figure out which changes accompany endothelial aging, which may lead to a decline in vascular function, and which reflect the adaptation of cells to a changing environment,” de Rooy concludes.