Abstract
The routing of blood flow throughout the brain vasculature is precisely controlled by mechanisms that serve to maintain a fine balance between local neuronal demands and vascular supply of nutrients. We recently identified two capillary endothelial cell (cEC)-based mechanisms that control cerebral blood flow in vivo: 1) electrical signaling, mediated by extracellular K(+)-dependent activation of strong inward rectifying K(+) (Kir2.1) channels, which are steeply activated by hyperpolarization and thus are capable of cell-to-cell propagation, and 2) calcium (Ca(2+)) signaling, which reflects release of Ca(2+) via the inositol 1,4,5-trisphosphate receptor (IP(3)R)-a target of G(q)-protein-coupled receptor signaling. Notably, Ca(2+) signals were restricted to the cell in which they were initiated. Unexpectedly, we found that these two mechanisms, which were presumed to operate in distinct spatiotemporal realms, are linked such that Kir2.1-dependent hyperpolarization induces increases in the electrical driving force for Ca(2+) entry into cECs through resident TRPV4 channels. This process, termed electrocalcium (E-Ca) coupling, enhances IP(3)R-mediated Ca(2+) release via a Ca(2+)-induced Ca(2+)-release mechanism, and allows focally induced hyperpolarization, including that initiated by ATP-dependent K(+) (K(ATP)) channels, to travel cell-to-cell via activation of Kir2.1 channels in adjacent cells, providing a mechanism for the "pseudopropagation" of Ca(2+) signals. Computational modeling supported the basic features of E-Ca coupling and provided insight into the intracellular processes involved. Collectively, these data provide strong support for the concept of E-Ca coupling and provide a mechanism for the spatiotemporal integration of diverse signaling pathways in the control of cerebral blood flow.