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The essential function of the circulatory system is to continuously and efficiently supply the O2 and nutrients necessary to meet the metabolic demands of every cell in the body, a function in which vast capillary networks play a key role. Capillary networks serve an additional important function in the central nervous system: acting as a sensory network, they detect neuronal activity in the form of elevated extracellular K⁺ and initiate a retrograde, propagating, hyperpolarizing signal that dilates upstream arterioles to rapidly increase local blood flow. Yet, little is known about how blood entering this network is distributed on a branch-to-branch basis to reach specific neurons in need. Here, we demonstrate that capillary-enwrapping projections of junctional, contractile pericytes within a postarteriole transitional region differentially constrict to structurally and dynamically determine the morphology of capillary junctions and thereby regulate branch-specific blood flow. We further found that these contractile pericytes are capable of receiving propagating K⁺-induced hyperpolarizing signals propagating through the capillary network and dynamically channeling red blood cells toward the initiating signal. By controlling blood flow at junctions, contractile pericytes within a functionally distinct postarteriole transitional region maintain the efficiency and effectiveness of the capillary network, enabling optimal perfusion of the brain.

Functional neuroimaging, such as fMRI, is based on coupling neuronal activity and accompanying changes in cerebral blood flow (CBF) and metabolism. However, the relationship between CBF and events at the level of the penetrating arterioles and capillaries is not well established. Recent findings suggest an active role of capillaries in CBF control, and pericytes on capillaries may be major regulators of CBF and initiators of functional imaging signals. Here, using two-photon microscopy of brains in living mice, we demonstrate that stimulation-evoked increases in synaptic activity in the mouse somatosensory cortex evokes capillary dilation starting mostly at the first- or second-order capillary, propagating upstream and downstream at 5–20 μm/s. Therefore, our data support an active role of pericytes in cerebrovascular control. The gliotransmitter ATP applied to first- and second-order capillaries by micropipette puffing induced dilation, followed by constriction, which also propagated at 5–20 μm/s. ATP-induced capillary constriction was blocked by purinergic P2 receptors. Thus, conducted vascular responses in capillaries may be a previously unidentified modulator of cerebrovascular function and functional neuroimaging signals.

Notch signalling in endothelial cells of the bone induces change in the capillaries and mesenchymal stem cells of the environment to support haematopoietic stem cell amplification. Age-linked changes in bone marrow Blood vessels in the bone marrow provide signals to the haematopoietic stem cells, however, how these signals modulate haematopoietic stem cell (HSC) function and change as an organism age is unclear. Ralf Adams and colleagues used imaging and cell-type-specific genetic mouse models to investigate the nature of vascular niches for HSCs in bone. They find that Notch signalling in bone endothelial cells induces change in the capillaries and mesenchymal stem cells of the environment to support HSC amplification. These signals are reduced in aged organisms, but activation of Notch can restore some of these properties. Elsewhere in this issue ( page 323 ), Tomer Itkin et al . show that the different functions of bone marrow endothelial cells are regulated by distinct types of endothelial blood vessels with different permeability properties, affecting levels of reactive oxygen species in their neighbouring stem cells. Blood vessels define local microenvironments in the skeletal system, play crucial roles in osteogenesis and provide niches for haematopoietic stem cells 1 , 2 , 3 , 4 , 5 , 6 . The properties of niche-forming vessels and their changes in the ageing organism remain incompletely understood. Here we show that Notch signalling in endothelial cells leads to the expansion of haematopoietic stem cell niches in bone, which involves increases in CD31-positive capillaries and platelet-derived growth factor receptor-β (PDGFRβ)-positive perivascular cells, arteriole formation and elevated levels of cellular stem cell factor. Although endothelial hypoxia-inducible factor signalling promotes some of these changes, it fails to enhance vascular niche function because of a lack of arterialization and expansion of PDGFRβ-positive cells. In ageing mice, niche-forming vessels in the skeletal system are strongly reduced but can be restored by activation of endothelial Notch signalling. These findings indicate that vascular niches for haematopoietic stem cells are part of complex, age-dependent microenvironments involving multiple cell populations and vessel subtypes.

Changes in neuronal activity are accompanied by the release of vasoactive mediators that cause microscopic dilation and constriction of the cerebral microvasculature and are manifested in macroscopic blood oxygenation level-dependent (BOLD) functional MRI (fMRI) signals. We used two-photon microscopy to measure the diameters of single arterioles and capillaries at different depths within the rat primary somatosensory cortex. These measurements were compared with cortical depth-resolved fMRI signal changes. Our microscopic results demonstrate a spatial gradient of dilation onset and peak times consistent with \"upstream\" propagation of vasodilation toward the cortical surface along the diving arterioles and \"downstream\" propagation into local capillary beds. The observed BOLD response exhibited the fastest onset in deep layers, and the \"initial dip\" was most pronounced in layer I. The present results indicate that both the onset of the BOLD response and the initial dip depend on cortical depth and can be explained, at least in part, by the spatial gradient of delays in microvascular dilation, the fastest response being in the deep layers and the most delayed response in the capillary bed of layer I.

Dynamic coupling of blood supply with energy demand is a natural brain property that requires signaling between synapses and endothelial cells. Our previous work showed that cortical arteriole lumen diameter is regulated by N-methyl-D-aspartate receptors (NMDARs) expressed by brain endothelial cells. The purpose of this study was to determine whether endothelial NMDARs (eNMDARs) regulate functional hyperemia in vivo. In response to whisker stimulation, regional cerebral blood flow (rCBF) and hemo-dynamic responses were assessed in barrel cortex of awake wild-type or eNMDAR loss-of-function mice using two-photon microscopy. Hyperemic enhancement of rCBF and vasodilation throughout the vascular network was observed in wild-type mice. eNMDAR loss of function reduced hyperemic responses in rCBF and plasma flux in individual vessels. Discovery of an endothelial receptor that regulates brain hyperemia provides insight into how neuronal activity couples with endothelial cells.

Neuronal activity is thought to communicate to arterioles in the brain through astrocytic calcium (Ca²⁺) signaling to cause local vasodilation. Paradoxically, this communication may cause vasoconstriction in some cases. Here, we show that, regardless of the mechanism by which astrocytic endfoot Ca²⁺ was elevated, modest increases in Ca²⁺ induced dilation, whereas larger increases switched dilation to constriction. Large-conductance, Ca²⁺-sensitive potassium channels in astrocytic endfeet mediated a majority of the dilation and the entire vasoconstriction, implicating local extracellular K⁺ as a vasoactive signal for both dilation and constriction. These results provide evidence for a unifying mechanism that explains the nature and apparent duality of the vascular response, showing that the degree and polarity of neurovascular coupling depends on astrocytic endfoot Ca²⁺ and perivascular K⁺.

Endothelial cell (EC) Ca ²⁺-activated K channels (SK Cₐ and IK Cₐ channels) generate hyperpolarization that passes to the adjacent smooth muscle cells causing vasodilation. IK Cₐ channels focused within EC projections toward the smooth muscle cells are activated by spontaneous Ca ²⁺ events (Ca ²⁺ puffs/pulsars). We now show that transient receptor potential, vanilloid 4 channels (TRPV4 channels) also cluster within this microdomain and are selectively activated at low intravascular pressure. In arterioles pressurized to 80 mmHg, ECs generated low-frequency (∼2 min ⁻¹) inositol 1,4,5-trisphosphate receptor-based Ca ²⁺ events. Decreasing intraluminal pressure below 50 mmHg increased the frequency of EC Ca ²⁺ events twofold to threefold, an effect blocked with the TRPV4 antagonist RN1734. These discrete events represent both TRPV4-sparklet- and nonsparklet-evoked Ca ²⁺ increases, which on occasion led to intracellular Ca ²⁺ waves. The concurrent vasodilation associated with increases in Ca ²⁺ event frequency was inhibited, and basal myogenic tone was increased, by either RN1734 or TRAM-34 (IK Cₐ channel blocker), but not by apamin (SK Cₐ channel blocker). These data show that intraluminal pressure influences an endothelial microdomain inversely to alter Ca ²⁺ event frequency; at low pressures the consequence is activation of EC IK Cₐ channels and vasodilation, reducing the myogenic tone that underpins tissue blood-flow autoregulation.

Increases in brain blood flow, evoked by neuronal activity, power neural computation and form the basis of BOLD (blood-oxygen-level-dependent) functional imaging. Whether blood flow is controlled solely by arteriole smooth muscle, or also by capillary pericytes, is controversial. We demonstrate that neuronal activity and the neurotransmitter glutamate evoke the release of messengers that dilate capillaries by actively relaxing pericytes. Dilation is mediated by prostaglandin E 2 , but requires nitric oxide release to suppress vasoconstricting 20-HETE synthesis. In vivo , when sensory input increases blood flow, capillaries dilate before arterioles and are estimated to produce 84% of the blood flow increase. In pathology, ischaemia evokes capillary constriction by pericytes. We show that this is followed by pericyte death in rigor, which may irreversibly constrict capillaries and damage the blood–brain barrier. Thus, pericytes are major regulators of cerebral blood flow and initiators of functional imaging signals. Prevention of pericyte constriction and death may reduce the long-lasting blood flow decrease that damages neurons after stroke. Neuronal activity relaxes pericytes, leading to capillary dilation and increased blood flow, before arterioles dilate, suggesting that pericytes initiate blood-oxygen-level-dependent (BOLD) functional imaging signals; pericytes constrict and die in rigor in ischaemia, which will cause a long-lasting blood flow decrease after stroke, and damage the blood–brain barrier. Blood flow response to neural activity Cerebral blood flow dynamics have long been linked to neural activity, and form the basis of BOLD (blood-oxygen-level-dependent) functional imaging. But how such blood flow changes are mediated has remained controversial. Here, David Attwell and colleagues reveal how neuronal activity can hyperpolarize pericytes, leading to their relaxation and capillary dilation. Capillary dilation is responsible for 84% of the blood increase linked to neural activity, so irreversible capillary closure due to pericyte death during ischaemia can injure the blood–brain barrier and exacerbate injury. Pericyte death under pathological conditions can be reduced if glutamate receptor signalling is inhibited. This work suggests that pericytes are major regulators of cerebral blood flow and may initiate BOLD imaging signals.

Neural activity in the brain is followed by localized changes in blood flow and volume. We address the relative change in volume for arteriole vs. venous blood within primary vibrissa cortex of awake, head-fixed mice. Two-photon laser-scanning microscopy was used to measure spontaneous and sensory evoked changes in flow and volume at the level of single vessels. We find that arterioles exhibit slow (<1 Hz) spontaneous increases in their diameter, as well as pronounced dilation in response to both punctate and prolonged stimulation of the contralateral vibrissae. In contrast, venules dilate only in response to prolonged stimulation. We conclude that stimulation that occurs on the time scale of natural stimuli leads to a net increase in the reservoir of arteriole blood. Thus, a \"bagpipe\" model that highlights arteriole dilation should augment the current \"balloon\" model of venous distension in the interpretation of fMRI images.

Arteriolar smooth muscle cells (SMCs) and capillary pericytes dynamically regulate blood flow in the central nervous system in the face of fluctuating perfusion pressures. Pressure-induced depolarization and Ca2+ elevation provide a mechanism for regulation of SMC contraction, but whether pericytes participate in pressure-induced changes in blood flow remains unknown. Here, utilizing a pressurized whole-retina preparation, we found that increases in intraluminal pressure in the physiological range induce contraction of both dynamically contractile pericytes in the arteriole-proximate transition zone and distal pericytes of the capillary bed. We found that the contractile response to pressure elevation was slower in distal pericytes than in transition zone pericytes and arteriolar SMCs. Pressure-evoked elevation of cytosolic Ca2+ and contractile responses in SMCs were dependent on voltage-dependent Ca2+ channel (VDCC) activity. In contrast, Ca2+ elevation and contractile responses were partially dependent on VDCC activity in transition zone pericytes and independent of VDCC activity in distal pericytes. In both transition zone and distal pericytes, membrane potential at low inlet pressure (20 mmHg) was approximately −40 mV and was depolarized to approximately −30 mV by an increase in pressure to 80 mmHg. The magnitude of whole-cell VDCC currents in freshly isolated pericytes was approximately half that measured in isolated SMCs. Collectively, these results indicate a loss of VDCC involvement in pressure-induced constriction along the arteriole-capillary continuum. They further suggest that alternative mechanisms and kinetics of Ca2+ elevation, contractility, and blood flow regulation exist in central nervous system capillary networks, distinguishing them from neighboring arterioles.