Pericytes put the squeeze on cognition: Like a computer, the brain needs a reliable source of power, which is provided as oxygen and glucose in the blood. However, in many neurological disorders this energy supply is disrupted. Brain blood flow is controlled by adjustment of the diameters of the vessels supplying the blood. Nortley et al. found that, both in humans developing Alzheimer's disease (AD) and in a mouse model of AD, brain capillaries become squeezed by pericytes (see the Perspective by Liesz). By defining the underlying mechanism, they suggest potential targets for therapy in early AD. Science , this issue p. eaav9518 ; see also p. 223

Pericytes, spatially isolated contractile cells on capillaries, have been reported to control cerebral blood flow physiologically, and to limit blood flow after ischaemia by constricting capillaries and then dying. Paradoxically, a recent paper dismisses the idea of pericytes controlling cerebral blood flow, despite confirming earlier data showing a role for pericytes. We show that these discrepancies are apparent rather than real, and depend on the new paper defining pericytes differently from previous reports. An objective definition of different sub-classes of pericyte along the capillary bed is needed to develop novel therapeutic approaches for stroke and disorders caused by pericyte malfunction.

Active neurons increase their energy supply by dilating nearby arterioles and capillaries to increase blood flow, but the mechanisms underlying neurovascular coupling are debated. In this paper, the authors show that different calcium-dependent signaling pathways regulate blood flow at the level of capillary pericytes and arteriole smooth muscle. Active neurons increase their energy supply by dilating nearby arterioles and capillaries. This neurovascular coupling underlies blood oxygen level–dependent functional imaging signals, but its mechanism is controversial. Canonically, neurons release glutamate to activate metabotropic glutamate receptor 5 (mGluR5) on astrocytes, evoking Ca2+ release from internal stores, activating phospholipase A2 and generating vasodilatory arachidonic acid derivatives. However, adult astrocytes lack mGluR5, and knockout of the inositol 1,4,5-trisphosphate receptors that release Ca2+ from stores does not affect neurovascular coupling. We now show that buffering astrocyte Ca2+ inhibits neuronally evoked capillary dilation, that astrocyte [Ca2+]i is raised not by release from stores but by entry through ATP-gated channels, and that Ca2+ generates arachidonic acid via phospholipase D2 and diacylglycerol lipase rather than phospholipase A2. In contrast, dilation of arterioles depends on NMDA receptor activation and Ca2+-dependent NO generation by interneurons. These results reveal that different signaling cascades regulate cerebral blood flow at the capillary and arteriole levels.

Astrocyte endfeet enwrap the entire vascular tree within the central nervous system, where they perform important functions in regulating the blood-brain barrier (BBB), cerebral blood flow, nutrient uptake, and waste clearance. Accordingly, astrocyte endfeet contain specialized organelles and proteins, including local protein translation machinery and highly organized scaffold proteins, which anchor channels, transporters, receptors, and enzymes critical for astrocyte-vascular interactions. Many neurological diseases are characterized by the loss of polarization of specific endfoot proteins, vascular dysregulation, BBB disruption, altered waste clearance, or, in extreme cases, loss of endfoot coverage. A role for astrocyte endfeet has been demonstrated or postulated in many of these conditions. This review provides an overview of the development, composition, function, and pathological changes of astrocyte endfeet and highlights the gaps in our knowledge that future research should address.