Brain Capillary Ion Channels: Physiology and Channelopathies.

The brain relies on an intricate vascular network to deliver oxygen and nutrients through functional hyperemia, a process critical for matching blood flow to neuronal activity. This review explores the roles of ion channels in brain capillary endothelial cells and pericytes, focusing on their contributions to neurovascular coupling. Key endothelial ion channels, including Kir2.1, K_ATP, transient receptor potential (TRP) vanilloid 4 (TRPV4), TRP ankyrin 1 (TRPA1), and Piezo1, regulate membrane potential and calcium dynamics, facilitating rapid electrical and chemical signaling that modulates blood flow. Pericytes, categorized as ensheathing and thin strand, express ion channels such as K_ATP, voltage-gated calcium channels, canonical TRP channels (TRPCs), and TMEM16A, which govern contractility and orchestrate blood flow responses. Additionally, we discuss channelopathies in conditions like Alzheimer's disease, cerebral small vessel diseases, hypertension, and ischemic stroke, where ion channel dysfunction impairs brain blood flow regulation. Emerging evidence underscores the therapeutic potential of targeting capillary ion channels to restore neurovascular function in these disorders.