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 n evolutionary success of the Microcirculation mammalian brain is its higher Pericyte Ametabolic capacity compared to Pericyte 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 X-section X-section more oxygen and glucose than is possible Arteriole Venule Capillary pericyte in lower phylogenetic organisms, such 2P Pericyte relaxation Pericyte contraction as reptiles and birds, which have larger L-type Ca2+ nucleated red blood cells (RBCs)1. However, channel ? Na+ a susceptibility of the mammalian brain is Actin depolymerization ChR2 that metabolic supply–demand mismatch Ca2+ has severe functional consequences, as seen ? during stroke, seizure, spreading depression, CO2 ROS/RNS Actin polymerization and several types of dementia. Actin Endothelium Within mammals, the volume of Rho Kinase 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 capillaries2, but to what extent capillaries are capable of actively controlling flow resistance by Capillary constriction changing diameter is a long-standing debate. Capillary Canonically, vascular smooth muscle cells dilation (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 Fig. 1 | Thin-strand pericytes provide slow regulation of capillary tone. Capillary pericytes with a by pericytes, are at the center of scientific thin-strand morphology are located on high-order capillaries (top center). These cells contain low ‘turbulence’ over their exact contribution to amounts of α-SMA, but enough to generate tension on the capillary wall when polymerized and to CBF and even how pericytes are defined3. set resting capillary diameter (bottom). Optogenetic stimulation (2P) elevates intracellular Ca2+ and It has been repeatedly demonstrated that free radical production, which together activate Rho-kinase to promote actin filament assembly and the initial, transitional segments of ‘small actomyosin coupling. The force generated cinches the endothelium and narrows the capillary lumen vessels’ arising from penetrating arterioles (right). Actin depolymerization reduces pericyte tension and dilates the underlying capillary, as seen in the neocortex can change diameter by during mild hypercapnia (left). X-section, cross-section; ROS, reactive oxygen species; RNS, reactive contractile VSMC–pericyte hybrid cells nitrogen species. called ensheathing pericytes4,5. In contrast, the greater population of ‘thin-strand’ pericytes found in more distal capillary all microvasculature, were claimed to be new study by Hartmann et al.8 in Nature segments (more than four branch orders passive6 or not actively contributing to Neuroscience advances our view by off the penetrator) and covering 96% of physiological cerebral perfusion7. The demonstrating that distal capillary pericytes NATURE NEUROSCIENCE | www.nature.com/natureneuroscience news & views provide vascular tone and slowly modulate important aspect of the constrictive pericyte is whether low α-SMA-containing capillary flow resistance in vivo. This finding will response is reversibility. Indeed, capillary pericytes contribute to functional hyperemia catalyze future work on the physiological diameter recovered to baseline over minutes by reducing capillary tone when neuronal functions of brain capillary beds, as well as after optogenetic activation, contrary to activity increases. Both VSMCs and the translational potential of pericytes in the rapid recovery (seconds) of upstream ensheathing pericytes rapidly relax when CBF-associated diseases and conditions. vascular segments. This indicates an active, local neurons are activated4,5, but active Cleared mouse cortical tissue was used albeit slow, bidirectional control of capillary dilation of distal capillaries is controversial, for immunostaining of α-smooth muscle diameter by pericytes. as one study reported no diameter response actin (SMA), an essential component An important question is whether to sustained, 30 s sensory stimulation6, of contractility. Staining confirmed that these slow pericyte responses exist during while a more recent publication found rapid α-SMA is undetectable in distal capillary physiologically relevant challenges. dilations and constrictions to brief retinal pericytes of the mouse cortex. Undeterred, Carbon dioxide, the byproduct of aerobic stimulation (although it is unclear what type the authors explored what happens to metabolism, is well known to increase CBF of pericyte was studied)12. If not functional capillary diameter when individual when elevated in the blood or in brain hyperemia, perhaps capillary pericytes help channelrhodopsin-2 (ChR2)-expressing parenchyma. Hartmann et al. found that redistribute tissue O2 regionally to groups pericytes (under the platelet-derived growth the inhalation of 5% CO2 for 6 min elicited of neurons experiencing higher or lower factor receptor beta (PDGFR-β) promoter) a transient dilation of precapillary arterioles metabolic demands on slower timescales, are selectively light-activated for 1 min and more gradual dilation in capillaries, such as during plastic changes. Alternatively, through a closed cranial window over the confirming the observations of recent actin polymerization in retinal pericytes was sensory cortex of mice. They optically studies10,11. Likewise, capillaries constricted evoked by norepinephrine injection9; thus, stimulated one pericyte at a time to avoid back to baseline more slowly than upstream interrogating the contribution of ascending activating proximal contractile cells, arterioles after the CO2 challenge. noradrenergic fibers from the locus which can indirectly change downstream Finally, Hartmann and colleagues coeruleus to pericyte tone control could be blood flow in the investigated capillaries. aimed to explore the physiological role of a promising approach. Understanding how In contrast to previous attempts, where capillary pericytes at rest by examining other cell types in the vicinity of pericytes— ChR2-activation of pericytes for less than 20 the consequences of pericyte loss. They RBCs, endothelial cells, astrocytes, and s had no effect on capillary diameter6, they monitored capillary diameter 3 days after microglia—could regulate their tone will observed slow, progressive vessel contraction single pericytes were selectively killed also be informative. Finally, the transient (~20%) adjacent to both the pericyte soma using a high-energy laser beam focused on dilation of capillary pericytes to a relatively and far-extending processes along the their cell bodies. This two-photon optical mild CO2 challenge suggests that pericytes capillary, with a subsequent decrease in RBC ablation resulted in an isolated enlargement respond to metabolic signals. Contradicting velocity and flux (blood cells per second). of the capillary lumen and doubled RBC this, a spreading wave of cortical This constriction had much slower (2.5×) flux at sites that were previously wrapped depolarization, which is accompanied kinetics than those recorded by optogenetic by pericytes. Focusing the laser adjacent by a massive release of glutamate, K+, activation of upstream ensheathing pericytes to pericytes had no such effect. As most metabolites, and vasoactive substances (Fig. 1). Additional work to exclude the pericyte somata are integral parts of leading to large arteriole diameter changes, possibility of artifacts from pericyte swelling the capillary wall, phototoxicity might did not elicit tone changes in capillary and phototoxicity revealed that capillary have extended to immediately adjacent pericytes6. constriction occurred irrespective of the endothelial cells and astrocyte endfeet. To In providing convincing evidence of the chosen anesthetic, developed similarly at address this potential caveat, they targeted regulatory effects of pericytes on capillary various cortical depth by matching laser ‘bridging’ and ‘floating’ pericytes (cell tone, these findings highlight new directions powers, was not accompanied by upstream bodies located in the capillary wall or in the and potential targets for CBF-associated precapillary constriction, preceded the drop parenchyma, respectively) that contacted brain diseases. In the context of stroke, of RBC flux, and was negligible in transgenic remote capillary segments with far-reaching ischemia-reperfusion constricts and can kill control mice. RBC stalling was also observed processes12 and were able to reproduce the ensheathing pericytes4,13, but it is disputed in a third of capillaries constricted by ChR2 same phenomena: capillary regions covered whether distal capillaries constrict12,14 activation.