How blood vessels restructure under pressure

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Ca2+ influx into vascular smooth muscle cells through Cav1.2 within caveolae due to hypertension activates a pathway leading to inflammation and vascular remodeling. This in turn causes atherosclerosis. The CaMKK2 protein is a potential drug target to prevent this process. Photo credit: Yoshiaki Suzuki of NCU, Japan. Proceedings of the National Academy of Sciences

High blood pressure, or hypertension, is a very common condition that can result from physical activity, stress, or certain disorders. Unfortunately, persistent high blood pressure can cause long-lasting changes in the structure of vascular smooth muscle cells (the cells that make up the walls of blood vessels) through a process called ‘vascular remodeling’. If left unchecked, this restructuring can stiffen artery walls, which lose their ability to adjust their size appropriately. This, in turn, leads to atherosclerosis and increases the risk of cerebrovascular disease.

Why and how high blood pressure triggers vascular remodeling is not entirely clear. Scientists have shown that macrophages, a type of white blood cell that kills foreign bodies, are involved in the transformation. In particular, the macrophages accumulate within the blood vessel walls from outside the vessels and cause chronic inflammation. However, the underlying mechanism orchestrating this process remains unknown.

With this in mind, researchers from Japan and Canada recently investigated a mechanism known as “excitation-transcription (ET) coupling” in vascular smooth muscle cells in a new study. By unveiling the mysteries behind ET coupling in these cells through experiments ranging from single cells to whole organisms, they successfully linked the ET coupling mechanism to vascular remodeling. The study, published in Proceedings of the National Academy of Sciences (PNAS)was led by Junior Associate Professor Yoshiaki Suzuki, Hisao Yamamura and Yuji Imaizumi from Nagoya City University, Japan, and Gerald W. Zamponi and Wayne R. Giles from the University of Calgary, Canada.

It is known that different types of cells undergo ET coupling. In neurons, for example, an excitation in the form of calcium ions (ca2+), which enters the cell via calcium channels, activates certain transcription factors and enzymes. These in turn trigger the transcription of various genes. Although ET coupling also occurs in vascular smooth muscle cells after an influx of Ca2+ Under high pressure, not much was known about how it happens, what genes are triggered, and what role it plays in our bodies.

The researchers attempted to answer these questions by focusing on caveolae, small structures resembling depressions that are widespread on the cell membrane. Through detailed experiments in single cells, cell cultures and live mice, the team found that a specific protein complex found in caveolae plays a key role in ET coupling in vascular smooth muscle cells.

They proved that this complex, called Cav1.2/CaMKK2/CaMK1a, is formed in caveolae and both CaMKK2 and CaMK1a are directly activated by Ca2+ Entry by approxv1.2 if they are given certain stimuli, e.g. B. high pressure exposed. In addition, they showed that this complex activates a signaling pathway that phosphorylates a transcription factor called CREB, ultimately leading to increased transcription of multiple genes.

By looking in detail at the genes promoted by ET linkage and observing their effects when blocked or amplified, the researchers made some important discoveries. First, some of these genes were implicated in chemotaxis, the phenomenon in which cell movement is triggered and directed by chemical stimuli. This helped explain the accumulation of macrophages in blood vessel walls from outside the vessels.

In addition, these genes promoted remodeling of the “medial” artery layer, which contains vascular smooth muscle cells and controls blood flow by contraction and expansion. “Taken together, our results explain how high pressure-induced ET coupling in vascular smooth muscle cells can modulate macrophage migration and subsequent inflammation, altering vascular structure,” explains Dr. Suzuki.

The results of this study have important implications for antihypertensive drugs. On the one hand, they explain why drugs such as nicardipine, a classic calcium channel blocker, prevent vascular remodeling and the progression of arteriosclerosis. This not only fills an important knowledge gap in medicine, but also presents several potential drug targets to treat or prevent vascular remodeling, such as: B. the components of the Cav1.2/CaMKK2/CaMK1a complex.

“About 40 million people in Japan alone have hypertension and are at high risk of stroke, end-stage renal failure and vascular dementia,” says Dr. Suzuki, “Understanding the mechanisms behind atherosclerosis is therefore very important for reducing the incidence, progression and recurrence of cerebrovascular disease and prolonging healthy life expectancy.”

Let’s hope this new information will lead to better treatments for high blood pressure and atherosclerosis in the near future.

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More information:
Yoshiaki Suzuki et al, A molecular complex of Ca v 1.2/CaMKK2/CaMK1a in caveolae is responsible for vascular remodeling via excitation-transcription coupling, Proceedings of the National Academy of Sciences (2022). DOI: 10.1073/pnas.2117435119

Provided by Nagoya City University

Citation: Understanding Arteriosclerosis: How Blood Vessels Restructure Under Pressure (2022 April 22) Retrieved April 22, 2022 from

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