Dysregulated Feedback Between Smooth Muscle and Extracellular Matrix as a Cause of Vascular Stiffening

Researchers here identify a point of intervention in the age-related dysregulation of smooth muscle cell activity and surrounding extracellular matrix structure in blood vessel walls. Blood vessels stiffen with age, which leads to hypertension and consequent pressure damage to delicate structures throughout the body. The damage caused by hypertension is an important component of aging, a significant contribution to loss of function and mortality. Loss of elastin, cross-linking of extracellular matrix molecules, and the chronic inflammation generated by senescent cells are all known to contribute to vascular stiffening. Linking together various causes and consequences of aging are the diverse mechanisms of cell signaling and regulation of cell behavior, a layer of greater complexity. That complexity makes it challenging to piece together exactly how individual discoveries relate to one another, so the work noted here stands in isolation, with further research needed in order to better understand it in the broader context.

The muscle cells in healthy blood vessels are elastic and can stretch like rubber bands, allowing high volumes of blood to pump through. When the blood vessel tissues lose their elasticity, the vessels stiffen, forcing the heart to work harder to pump blood throughout the body. While diet, exercise and medication can improve overall heart health, there are no drugs on the market to treat underlying stiffening in blood vessels.

Most research into blood vessel stiffening has focused on the material surrounding the living cells - called the extracellular matrix - as the most important contributor to this condition. However, researchers now lay out evidence that smooth muscle cells independently contribute to vascular stiffening. To study this connection, the researchers first had to cut the line of communication between cells and the surrounding matrix. They used a gene editing tool called CRISPR to breed mice lacking the gene that produces transglutaminase (TG2), an enzyme enabling this crosstalk to take place.

Compared with mice that had normal TG2 production, the researchers found that in mice with no TG2 - where the crosstalk between the matrix and vascular smooth muscle cells was uncoupled - the development of vascular stiffening was reduced by nearly 70% at age 15 months. This is old age for a mouse and, generally, the time when blood vessels stiffen. The researchers say this indicates smooth muscle cells independently contribute to vascular stiffening, and that crosstalk influences vascular aging. Researchers suspect that severe vascular stiffening, like that seen in humans of old age, could be caused by out-of-control feedback between smooth muscle cells and their surrounding matrix.

Link: https://www.hopkinsmedicine.org/news/newsroom/news-releases/stiff-blood-vessels-linked-to-enzyme-that-fosters-cell-chatter

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