Can Creating New Blood Vessel Cells Slow Vascular Aging? A Look at Recent Research

As Thomas Sydenham, the so-called English Hippocrates, said in the 17th century, “A man is as old as his arteries.” 

For the first time, researchers have uncovered a successful method for studying the aging process of blood vessels, which encompasses arteries, veins, and capillaries. This innovative mechanism, which uses cellular modeling, could lead to new treatments to slow vascular aging. 

Age-related damage to the vasculature — the network of blood vessels connecting the heart to other organs — is a risk factor for several diseases, leading to disability and mortality. These disorders include cardiovascular disease, impacting the heart’s blood vessels, and cerebrovascular disease, affecting the brain’s blood vessels. 

Therefore, any new research that can elucidate how and why vascular aging occurs has the potential to reduce the risk of these widespread diseases and slow the aging process.  

In this article, learn more about this recent study that found a way to create new blood vessel cells with the ultimate goal of slowing down vascular aging and extending healthspan — the years of life lived without disease — and, potentially, lifespan.  

Background: A Look At Vascular Aging 

When the vascular system ages, blood vessels become hardened, calcified, and leaky, and veins and arteries become less elastic. These changes contribute to high blood pressure and an increased risk of heart disease. 

In the past, researchers have only observed these changes visually, rather than measuring the molecular effects of aging. Collecting blood vessel cells is highly invasive, which is why research on the cellular markers of vascular aging in humans is limited. Previous research has involved animal models for studying these biological markers of aging in tissues that can’t be easily accessed in humans. 

Another method that previous research has employed is the use of pluripotent stem cells, which are “master cells” that can reprogram to become any type of cell.

Although this process can effectively create new blood vessel cells, researchers found that this reprogramming wipes out any age-related molecular changes that may have occurred. Essentially, the new cells are reset to have only “young” properties and cellular signatures. This reset means that the cellular vascular aging process cannot be studied; therefore, therapeutic strategies to target age-related vascular disorders are also out of reach. 

Until now, when Salk Institute researchers have discovered a way to recreate human vasculature from skin cells without using the pluripotent stem cells that erase the molecular markers of aging. 

How Did the Researchers Create New Blood Vessel Cells?

The study, published in eLife in September 2020, was authored by researchers at the Salk Institute in San Diego. 

Previous research from the same team in 2015 explained how the researchers created aging brain cells from human skin cells. As the brain is another organ that is difficult to access and study, this method produced cells with the hallmark characteristics of older people’s brains, allowing scientists to more easily research age-related neurodegenerative diseases, like Alzheimer’s disease.

In this study, the Salk researchers utilized the same method to induce vascular cells without pluripotent stem cells. Skin cells called fibroblasts were taken from three young donors (19-30 years old), three older donors (62-87 years old), and eight patients with Hutchinson-Gilford progeria syndrome (HGPS). Also known as progeria, HGPS is a rare genetic disorder that causes premature aging in early life, which is why it’s commonly used to study biological markers of aging.

Researchers then directly reprogrammed the fibroblasts to become induced vascular endothelial cells (iVECs) and induced smooth muscle cells (iSMCs). 

Vascular endothelial cells make up a single-cell layer along the blood vessels’ inner lining; damage to these cells precedes cardiovascular disease. Smooth muscle cells surround the endothelial cells and are involved in blood vessel constriction and dilation, playing a role in developing atherosclerosis and hypertension when damaged. 

What Were the Results? 

The researchers found that the iVECs and iSMCs showed clear markers of aging and expression of genes involved with blood vessel calcification and inflammation. 

Specifically, the iVECs from older donors showed an increased expression of the genes GSTM1 and PALD1, linked to oxidative stress, inflammatory pathways, and inhibition of endothelial junction stability. 

They also looked at levels of the protein BMP-4 (Bone Morphogenetic Protein 4), which is involved in blood vessel calcification when overexpressed. BMP-4 levels were higher in the older donors’ cells compared to younger.

However, BMP-4 levels were significantly higher in HGPS patients than older donors, indicating that BMP-4 is also involved in the process of accelerated aging.

After discovering the importance of BMP-4 levels in aging and cardiovascular health, the researchers blocked the protein to see the impact on the aged vascular cells. 

They found that in donors with vascular disease, the use of targeted antibodies to block BMP-4 led to a reduction in vascular leakiness, which commonly occurs in aging blood vessels.

The results indicate that new therapies for both vascular aging and HGPS may be on the horizon. Researchers will now be able to study the impact of various vasculature treatments using this new direct-conversion method of fibroblasts into vascular cells. Targeting BMP-4 may also be a new strategy to reduce the damage seen in both HGPS and aging human cardiovascular systems.  

Key Takeaway: What Does This Research Mean?

• Salk Institute researchers have now successfully converted fibroblasts into both neurons and vascular cells and likely will continue to apply this process to other cell types affected by aging.  
• This process is novel based on its direct-conversion method, which takes fibroblasts and directly converts them into vascular cells without using pluripotent stem cells, allowing for better research on aging cells, as the stem cells wipe out the molecular markers of aging. 
• Future research could use this direct-conversion method to reduce age-related vascular damage, thereby reducing the risk of cardiovascular and cerebrovascular diseases and extending healthspan and, potentially, lifespan. 

References: 

Bersini S, Schulte R, Huang L, Tsai H, Hetzer MW. Elife. 2020;9:e54383. Published 2020 Sep 8. 

Mertens J, Paquola ACM, Ku M, et al. Cell Stem Cell. 2015;17(6):705-718.

Ungvari Z, Tarantini S, Donato AJ, Galvan V, Csiszar A. Circ Res. 2018;123(7):849-867. 

Wei X, Wu W, Li L, et al. Biomed Res Int. 2018;2018:8371604. Published 2018 Apr 12.