Blood vessels in the retrotrapezoid nucleus (RTN), a small region in the brainstem that controls breathing, constrict when carbon dioxide levels rose, a new study from the University of Connecticut shows. In contrast, blood vessels from slices of the brain’s cortex dilate in response to high carbon dioxide, as do those in the rest of the body.

We breathe to help us take oxygen into the body and remove carbon dioxide. Our cells use the oxygen to break down food to release energy, and as they do so they produce carbon dioxide as a waste product.

Cells release this carbon dioxide back into the bloodstream so that it can be transported to the lungs to be breathed out. Carbon dioxide also makes the blood more acidic; if the blood becomes too acidic, tissues and organs may not work properly.

The brain uses roughly 25% of the oxygen consumed by the body and is particularly sensitive to the levels of gases and acidity in the blood. It has been known for more than a century that increased carbon dioxide causes blood vessels in the brain to widen, allowing the excess carbon dioxide to be carried away quickly.

More recent work has shown that increased carbon dioxide also activates neurons called respiratory chemoreceptors. These in turn activate the brain centers that drive breathing, causing us to breathe more rapidly to help us remove surplus carbon dioxide.

Paradoxical Mystery

But this scenario contains a paradox.

If high levels of carbon dioxide cause widening of the blood vessels in the brain regions that contain respiratory chemoreceptors, this should, in theory, wash out that important stimulus, reducing the drive to breathe. So how does the brain prevent this unhelpful response?

By studying the brains of adult rats, UConn physiologist Dan Mulkey and his team showed that different rules apply to the brain centers that control breathing compared to other areas of the brain.

In one such region, the retrotrapezoid nucleus, if the blood becomes too acidic, support cells called astrocytes release chemical signals called purines. This counteracts the tendency of high carbon dioxide levels to widen blood vessels in this region, and instead causes these vessels to become narrower.

“This is a big change in how we think about breathing,” Mulkey says.

And about blood vessels. Even in a single organ like the brain, the purpose of blood flow is not the same everywhere.

This purine driven mechanism ensures that local levels of carbon dioxide in respiratory brain centers remain in tune with the demands of local networks, thereby maintaining the drive to breathe. The next challenges are to identify the molecular mechanisms that control the diameter of blood vessels in brain regions containing respiratory chemoreceptors, and to find out whether drugs that modulate these mechanisms have the potential to treat some respiratory conditions.

The study was supported by funds from the National Institutes of Health, the Totman Medical Research Trust, Fondation Leduca, EC Horizon 2020, Connecticut Department of Public Health, and public funding from the São Paulo Research Foundation.

Virginia E Hawkins, Ana C Takakura, Ashley Trinh, Milene R Malheiros-Lima, Colin M Cleary, Ian C Wenker, Todd Dubreuil, Elliot M Rodriguez, Mark T Nelson, Thiago S Moreira, Daniel K Mulkey Purinergic regulation of vascular tone in the retrotrapezoid nucleus is specialized to support the drive to breathe eLife 2017;6:e25232

Image: Endothelial cells lining the vessel (purple), red blood cells (red), and neurons (orange). Astrocytes are not identified in this image, but would be among the greyed background cells. Credit: Dan Mulkey/UConn

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