Sustained neuronal activity requires similarly sustained blood flow, in a phenomenon called neurovascular coupling. Disruption of neurovascular coupling has been linked to Alzheimer’s disease, cerebral small vessel disease, and age-related cognitive decline. But what are the molecular signals that keep this important signaling on track? Boris Lavenderos and colleagues have found that calcium ion (Ca2+) signaling mediated by ORAI1 or ORAI3 and the Ca2+ sensor STIM1 in capillary endothelial cells keeps arterioles open and sending blood to the brain during prolonged neuronal activity. Arterioles are blood vessels that branch out from larger arteries to connect with much smaller capillaries, acting as a sort of control valve for blood flow by dynamically changing their diameter. Lavenderos et al. also found that deficiencies of ORAI or STIM1 proteins in endothelial cells in mice could lead to anxiety-like behaviors and cognitive changes like those seen in early-stage vascular dementia. The new research confirms that “capillary communication appears not to be a purely passive electrical process, but an actively reinforced signaling network,” as Fabrice Dabertrand discusses in a related Focus.