A team of UVM scientists led by Mark Nelson, Ph.D., of the Larner College of Medicine at the University of Vermont, has discovered a new mechanism that is reshaping our understanding of how blood flow is regulated in the brain. The study, published in The work of the National Academy of Sciences (PNAS)a peer-reviewed journal of the National Academy of Sciences (NAS), introduces Electro-Calcium (E-Ca) Coupling, a process that integrates electrical and calcium signaling in brain capillaries to ensure precise blood flow delivery to active neurons.
In the human body, blood is delivered to the brain from surface arteries via penetrating arterioles, or very small blood vessels branching off arteries, and hundreds of kilometers of capillaries, which greatly increase the perfusion area. The brain – a highly metabolically demanding organ that does not have substantial energy reserves – maintains constant blood flow despite blood pressure fluctuations (autoregulation), but depends on an on-demand delivery process in which neuronal activity causes a local increase in blood flow to selectively deliver oxygen and nutrients to active distribution areas.
This use-dependent increase in local blood flow (functional hyperemia), mediated by mechanisms collectively termed neurovascular coupling (NVC), is essential for normal brain function and represents the physiological basis for functional magnetic resonance imaging. Furthermore, cerebral blood flow (CBF) deficits, including functional hyperemia, are an early feature of small vascular diseases (SVDs) of the brain and Alzheimer’s disease, long before overt clinical symptoms.”
Mark Nelson, Ph.D., of the Larner College of Medicine, University of Vermont
Cerebral blood supply depends on mechanisms such as electrical signaling, which propagates through capillary networks to upstream arterioles to deliver blood, and calcium signaling, which refines local blood flow. For years it was thought that these mechanisms would work independently. However, Nelson’s research shows that these systems are deeply connected via E-Ca coupling, where electrical signals enhance calcium entry into cells, amplify localized signals and extend their influence to neighboring cells.
The study showed that electrical hyperpolarization in capillary cells spreads rapidly through activation of capillary endothelial Kir2.1 channels, specialized proteins in the cell membrane that detect changes in potassium levels and amplify electrical signals by passing them from cell to cell. This creates a wave-like electrical signal that travels through the capillary network. At the same time, calcium signals initiated by IP3 receptors – proteins located in the membranes of intracellular stores – release stored calcium in response to specific chemical signals. This local release of calcium refines blood flow by inducing vascular responses. E-Ca coupling bridges these two processes, with the electrical waves generated by Kir2.1 channels enhancing calcium activity, creating a synchronized system that adjusts blood flow both locally and over greater distances.
Using advanced imaging and computer models, the researchers were able to observe this mechanism in action. They found that electrical signals in capillary cells increased calcium activity by 76%, significantly increasing its ability to influence blood flow. When the team mimicked brain activity by stimulating these cells, calcium signals increased by 35%, demonstrating how these signals travel through the capillary network. Interestingly, they found that the signals spread evenly throughout the capillary bed, balancing blood flow across all areas, without favoring one direction or the other.
“Recently, the UVM team also demonstrated that cerebral blood flow deficits in small vessel disease of the brain and Alzheimer’s disease can be corrected by an essential cofactor of electrical signaling,” Nelson said. “Current work indicates that calcium signaling can also be restored. The ‘Holy Grail,’ so to speak, is whether early restoration of cerebral blood flow in cerebral blood vessel disease slows cognitive decline.”
This discovery underlines the crucial role of capillaries in controlling blood flow in the brain. By identifying how electrical and calcium signals work together through electro-calcium coupling, the research sheds light on the brain’s ability to efficiently direct blood to areas of greatest demand for oxygen and nutrients. This is especially important because disturbances in blood flow are a hallmark of many neurological conditions, such as stroke, dementia and Alzheimer’s disease. Understanding the mechanisms of E-Ca coupling provides a new framework for investigating treatments for these conditions, potentially leading to therapies that restore or improve blood flow and protect brain health. This breakthrough also provides a deeper understanding of how the brain maintains its energy balance, which is critical for maintaining cognitive and physical function.