Atherosclerosis: How diseased blood vessels communicate with the brain
By Ludwig-Maximilians-Universität München
By Ludwig-Maximilians-Universität München
LMU scientists have been able to demonstrate for the first time that nerve signals are exchanged between arteries and the brain in atherosclerosis.
Laboratories worldwide are carrying out research into the disease atherosclerosis. However, their focus is on atherosclerotic plaques — deposits of cholesterol, fibrous tissue and immune cells that form on the inner layer of arteries. These plaques progressively constrict the lumen of the arteries, such that less oxygen can get to the body tissue. Heart attacks, strokes and peripheral occlusive disease (smoker’s leg) are among the known consequences.
“In recent decades, nobody has asked whether there is a direct connection between the artery and the brain — the obvious reason being that atherosclerotic plaques are not innervated,” says Dr. Sarajo K. Mohanta from the LMU Institute for Cardiovascular Prevention. But it is precisely such a connection that he has now managed to demonstrate together with Professor Andreas Habenicht, also from the LMU Institute for Cardiovascular Prevention, Prof. Christian Weber, director of the institute, and an international team. Crucial results were obtained by Professor Daniela Carnevale and Professor Giuseppe Lembo from the Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Sapienza University of Rome. Parts of the study were funded by LMU’s Cluster of Excellence SyNergy and the Collaborative Research Center 1123.
In Nature, the researchers report their findings about signals that are conveyed from the arteries containing plaques via nerves to the brain. After processing of the signals in the brain has taken place, signals make their way back to the blood vessel.
A completely new understanding of atherosclerosis
Some background information: The walls of arteries are made up of three components, an outer layer, a middle layer, and an inner layer. Plaques are found in the inner layer. They are not innervated by nerve fibers — a fact that has long been known. “As such, it did not occur to anyone to investigate whether the peripheral nervous system comes into contact with arteries in the case of atherosclerosis,” says Habenicht.
Since 2004, his research group has been investigating what happens on the outer wall of arteries in patients burdened with atherosclerosis. “After all, atherosclerosis is more than just a plaque, rather it is a chronic inflammatory disease of the entire artery — and relevant to our findings the outer layer of it,” adds Mohanta, who was the lead scientist in charge of the project.
The peripheral nervous system responds to such inflammation. Habenicht’s team discovered that molecular sensors known as receptors play a key role. Receptors are located in the outer layer of the vessels. They recognize where plaques are located and where vessels are inflamed by identifying the inflammatory messengers of the inflammation. Then they translate the inflammatory signals into electrical signals via nerves to the brain. The brain processes the signals and sends a stress signal back to the inflamed blood vessel. This negatively influences the inflammation, and the atherosclerosis gets worse.
Long-term prospects for treating causes of atherosclerosis
This previously unknown electrical circuit between the arteries and the brain is potentially of enormous significance. In an animal experiment, Carnevale severed the electrical connection between a diseased artery and the brain. Eight months later, she compared treated mice with mice that had not had this procedure. In the rodents that had had the experimental therapy, atherosclerosis was in fact less developed than in the control mice. “In the long term, we hope to be finally able to treat the causes of atherosclerosis,” says Mohanta, “although that may well be some way off yet.”
As their next step, the scientists want to find out how exactly the peripheral nervous system is organized — and what role other receptors play. There are also many signs that the interface between brain and diseased blood vessels is regulated by stress. Accordingly, Habenicht is planning to investigate neurobiological aspects: Which cells in the brain respond to signals from diseased blood vessels? And with which regions of the brain are these cells connected in turn?
Journal Reference: Sarajo K. Mohanta, Li Peng, Yuanfang Li, Shu Lu, Ting Sun, Lorenzo Carnevale, Marialuisa Perrotta, Zhe Ma, Benjamin Förstera, Karen Stanic, Chuankai Zhang, Xi Zhang, Piotr Szczepaniak, Mariaelvy Bianchini, Borhan R. Saeed, Raimondo Carnevale, Desheng Hu, Ryszard Nosalski, Fabio Pallante, Michael Beer, Donato Santovito, Ali Ertürk, Thomas C. Mettenleiter, Barbara G. Klupp, Remco T. A. Megens, Sabine Steffens, Jaroslav Pelisek, Hans-Henning Eckstein, Robert Kleemann, Livia Habenicht, Ziad Mallat, Jean-Baptiste Michel, Jürgen Bernhagen, Martin Dichgans, Giuseppe D’Agostino, Tomasz J. Guzik, Peder S. Olofsson, Changjun Yin, Christian Weber, Giuseppe Lembo, Daniela Carnevale, Andreas J. R. Habenicht. Neuroimmune cardiovascular interfaces control atherosclerosis. Nature, 2022; DOI: 10.1038/s41586-022-04673-6