news & views CAPILLARY PERICYTES A tense relationship between capillaries and pericytes Most of the cerebral microcirculation is comprised of capillaries that are lined with pericytes, but the infuence of pericytes on local blood fow was not previously established. A new study by Hartmann and colleagues uses selective optical ablation or activation to demonstrate that capillary pericytes exert both static and slow types of regulation on capillary diameter to afect fow, which are distinct from canonical rapid regulation by arteriole smooth muscle. Adam Institoris and Grant R. Gordon A n evolutionary success of the mammalian brain is its higher metabolic capacity compared to other types of animals. The neocortex of mammals relies upon small, deformable erythrocytes, tightly transiting an extremely dense capillary network. This enables the fueling of intense neuronal processing with more oxygen and glucose than is possible in lower phylogenetic organisms, such as reptiles and birds, which have larger nucleated red blood cells (RBCs) 1 . However, a susceptibility of the mammalian brain is that metabolic supply–demand mismatch has severe functional consequences, as seen during stroke, seizure, spreading depression, and several types of dementia. Within mammals, the volume of oxygenated blood that can reach brain cells per unit time is mostly determined by the flow resistance of the supplying vasculature. It is estimated that the majority of resistance originates from capillaries 2 , but to what extent capillaries are capable of actively controlling flow resistance by changing diameter is a long-standing debate. Canonically, vascular smooth muscle cells (VSMC) in arterioles can rapidly constrict or dilate the vessel lumen to regulate cerebral blood flow (CBF). In contrast, capillaries, comprised of endothelial cells wrapped by pericytes, are at the center of scientific ‘turbulence’ over their exact contribution to CBF and even how pericytes are defined 3 . It has been repeatedly demonstrated that the initial, transitional segments of ‘small vessels’ arising from penetrating arterioles in the neocortex can change diameter by contractile VSMC–pericyte hybrid cells called ensheathing pericytes 4,5 . In contrast, the greater population of ‘thin-strand’ pericytes found in more distal capillary segments (more than four branch orders off the penetrator) and covering 96% of all microvasculature, were claimed to be passive 6 or not actively contributing to physiological cerebral perfusion 7 . The new study by Hartmann et al. 8 in Nature Neuroscience advances our view by demonstrating that distal capillary pericytes Capillary pericyte Na + Ca 2+ ROS/RNS Rho Kinase ChR2 Actin polymerization Actin depolymerization Pericyte contraction Pericyte relaxation Actin CO 2 L-type Ca 2+ channel ? ? X-section X-section Pericyte Pericyte Arteriole Venule 2P Microcirculation Capillary constriction Capillary dilation Endothelium Fig. 1 | Thin-strand pericytes provide slow regulation of capillary tone. Capillary pericytes with a thin-strand morphology are located on high-order capillaries (top center). These cells contain low amounts of α-SMA, but enough to generate tension on the capillary wall when polymerized and to set resting capillary diameter (bottom). Optogenetic stimulation (2P) elevates intracellular Ca 2+ and free radical production, which together activate Rho-kinase to promote actin filament assembly and actomyosin coupling. The force generated cinches the endothelium and narrows the capillary lumen (right). Actin depolymerization reduces pericyte tension and dilates the underlying capillary, as seen during mild hypercapnia (left). X-section, cross-section; ROS, reactive oxygen species; RNS, reactive nitrogen species. NATURE NEUROSCIENCE | www.nature.com/natureneuroscience