EXPRESS: Targeting the Neurovascular Interface: Endothelial Optogenetics as a New Frontier for Brain Circuit Interrogation

The advent of optogenetics has revolutionized neuroscience by enabling precise manipulation of neural circuits, solidifying a neuron-centric view of brain function. This perspective has increasingly expanded to encompass non-neuronal cells, with the optogenetic control of astrocytes, microglia, and pericytes revealing their active roles in information processing. Yet the vascular endothelium long regarded as a passive conduit has remained largely unexplored through this lens. Here we discuss the emerging field of endothelial optogenetics, which seeks to isolate the cell-autonomous signaling capacity of brain endothelial cells, distinct from their hemodynamic functions. We explore the hypothesis that targeted optical stimulation of these cells may evoke calcium-dependent release of angiocrine factors, establishing a vasculature-to-parenchyma signaling axis that directly modulates neuronal activity and behavior. This approach not only challenges the traditional neurovascular coupling paradigm but also offers transformative potential for reinterpreting neuroimaging data and developing novel therapies for neuropsychiatric and neurodegenerative disorders. By elevating the endothelium to the status of an active computational element, endothelial optogenetics promises to reshape our understanding of the brain as an integrated hemo-neural system.