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Proc Natl Acad Sci U S A. Dec 21, 2010; 107(51): 22290–22295.
Published online Dec 6, 2010. doi:  10.1073/pnas.1011321108
PMCID: PMC3009761

Pericytes in capillaries are contractile in vivo, but arterioles mediate functional hyperemia in the mouse brain


Modern functional imaging techniques of the brain measure local hemodynamic responses evoked by neuronal activity. Capillary pericytes recently were suggested to mediate neurovascular coupling in brain slices, but their role in vivo remains unexplored. We used two-photon microscopy to study in real time pericytes and the dynamic changes of capillary diameter and blood flow in the cortex of anesthetized mice, as well as in brain slices. The thromboxane A2 analog, 9,11-dideoxy-9α,11α-methanoepoxy Prostaglandin F2α (U46619), induced constrictions in the vicinity of pericytes in a fraction of capillaries, whereas others dilated. The changes in vessel diameter resulted in changes in capillary red blood cell (RBC) flow. In contrast, during brief epochs of seizure activity elicited by local administration of the GABAA receptor antagonist, bicuculline, capillary RBC flow increased without pericyte-induced capillary diameter changes. Precapillary arterioles were the smallest vessels to dilate, together with penetrating and pial arterioles. Our results provide in vivo evidence that pericytes can modulate capillary blood flow in the brain, which may be important under pathological conditions. However, our data suggest that precapillary and penetrating arterioles, rather than pericytes in capillaries, are responsible for the blood flow increase induced by neural activity.

Keywords: cerebral blood flow, neurovascular coupling, cortical spreading depolarization, electrophysiology

Gray matter of the brain has a very high metabolic activity, maintaining the energy requirements of information transfer and processing (1). In the brain, adaptation of regional blood flow to local increases in neuronal activity guarantees a spatially and temporally matched supply of substrates. In addition, this “neurovascular coupling” underlies noninvasive brain mapping techniques like functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) (2). The spatial and temporal acuity of these techniques depends on the degree by which the hemodynamic response overlaps with the activation of neural tissue and, ultimately, on the disposition of blood flow regulating elements.

The smooth muscle cells (SMCs) of arteries and arterioles are the canonical effectors of blood flow regulation. However, it has been proposed that control of blood flow may be exerted by pericytes located in the walls of capillaries, at the place where the metabolic demand occurs and could be most rapidly sensed (3). The contractility of cultured pericytes is well established and, of all organs, capillaries in the central nervous system (CNS) are endowed with the highest number of pericytes (4). Pericytes of the isolated retina have been shown to react to vasoactive substances (5). Recently, pericytes in cerebellar slice preparations were found to react with dilatations and constrictions to the application of different neurotransmitters, suggesting a general capacity of capillaries to increase blood supply locally (6). However, the behavior of brain pericytes in vivo has not been investigated and is difficult to predict from experiments performed in isolated tissue, in which the concerted response of the vascular network is disrupted, no transluminal pressure gradients exist, and tissue homeostasis is independent of blood supply. We used intravital two-photon laser scanning microscopy (TPLSM) of the brain cortex of green fluorescent protein (GFP) transgenic mice (7), in which the expression of GFP by endothelial cells and pericytes enabled the visualization of the capillary vessel wall. We studied in real time the reaction of capillary pericytes to application of the vasoconstrictor 9,11-dideoxy-9α,11α-methanoepoxy Prostaglandin F2α (U46619) and during functional hyperemia associated with bicuculline-induced neuronal activity or cortical spreading depolarization (CSD). We find that pericytes are contractile and capable of modulating cerebral blood flow (CBF) at the capillary level, but they do not play a major role in the process of neurovascular coupling.


Pericytes in Acute Brain Slice Preparations Constrict in Response to U46619.

Vascular cells in the brains of GFP transgenic mice were discerned by means of their GFP expression (Fig. 1). Pericytes were identified morphologically on the basis of their typical fusiform, protruding cell body and their expression of the marker proteins aminopeptidase-N (APN), platelet-derived growth factor-β (PDGFR-β), and α-smooth muscle actin (α-SMA) (Fig. 1 A, D, and E). GFP-expressing pericytes were negative for the endothelial cell marker platelet-endothelial cell adhesion molecule-1 (PECAM-1) (Fig. 1B) and the astrocyte marker glial fibrillary acidic protein (GFAP) (Fig. 1F). Pericytes were enclosed within the basement membrane of capillaries, but separated from endothelial cells by a membrane sheet (Fig. 1C). These features are hallmarks of brain pericytes (8). The characteristic morphology of a GFP-positive pericyte with circumferential processes arising from the cell body is shown in Fig. S1. To elucidate whether brain cortical pericytes possess contractile properties, we imaged capillaries in brain slices exposed to U46619, a TBXA2 receptor agonist and potent vasoconstrictor (Fig. 2A and Movies S1 and S2). The reaction to U46619 was concentration dependent, resulting in constrictions of up to 75 ± 12% of basal capillary diameter (P < 0.001, n = 11, Fig. 2B). The mean diameter changes were negatively correlated with the logarithmic concentration of U46619 (r = 0.99, P < 0.05). The U46619-induced constriction was partially reversed by addition of 1 μM SQ 29,548, a competitive TBXA2 receptor antagonist (Fig. 2D and Movies S1 and S2). Preincubation with SQ 29,548 completely prevented the effects of U46619 (Fig. 2C). The constrictions were localized in discrete sections of the capillaries. They either were sphincter-like (<10 μm, 53% of the cases) or encompassed longer vessel segments. Fifty-seven percent of the constrictions were localized to capillary bifurcations. Occasionally, a bulging of pericyte cell bodies occurred after superfusion with U46619 (Fig. 2A, Insets, and Movies S1 and S2). Importantly, capillary constrictions at pericyte bodies exceeded constrictions measured halfway between two pericyte bodies (median 84% vs. 95% of basal diameter, P < 0.005, n = 18 slices, Fig. 2E). In three cases, discrete capillary segments dilated adjacent to the constriction sites (Fig. 2E and Movie S2), suggesting increased capillary intraluminal pressure due to overall constriction. Our results indicate that pericytes in brain capillaries constrict in response to activation of TBXA2 receptors.

Fig. 1.
Pericytes can be visualized in the brains of GFP transgenic mice. (A) The small (~10 μm) spindle-shaped cell bodies protruding from the capillary wall and their processes were positive for the pericyte marker APN (arrowhead). (B) Negative ...
Fig. 2.
U46619 induces pericyte contraction in brain slice preparations. (A) TPLSM images of capillaries in slice, before or after superfusion with 100 nM U46619. Pericyte bodies (p) can be identified. Discrete constrictions along the vessel can be observed (arrowheads), ...

Pericyte Constrictions Induced by U46619 Occur in Vivo and Are Paralleled by Red Blood Cell (RBC) Perfusion Changes.

We next sought to determine whether similar changes could also be observed in vivo. To this end, we superfused 10 μM U46619 through a closed cranial window located over the parietal sensory cortex of anesthetized GFP transgenic mice. To study the dynamics of capillary reactivity, we imaged capillaries containing pericytes at 2-min intervals with TPLSM over a total period of ~1 h before and during the superfusion with 10 μM U46619 (five animals). In 7 of 14 capillaries thus investigated, we observed constrictions with morphological features similar to the constrictions found in the slice preparations (Movies S3 and S4).

To determine the efficacy of capillary diameter changes on capillary flow, we measured capillary diameters, RBC velocities, and flux before and after the superfusion with either vehicle (44 capillaries from five mice) or 10 μM U46619 (37 capillaries from five mice). Fig. 3A shows the constriction of a capillary at the site of a pericyte body. Changes in all parameters differed significantly between vehicle- and U46619-treated capillaries (median of the diameter changes, 104% vs. 96%, P < 0.001; RBC flux, 101% vs. 17%, P < 0.0001; RBC velocity, 97% vs. 27%, P < 0.001; Fig. 3B). Of note, all U46619-treated animals showed capillary dilatations and constrictions, which were accompanied by increases and decreases in flow parameters. We found a significant negative linear correlation between the pooled absolute differences in capillary diameters and the changes in RBC flow (r = 0.49, P < 0.001) and velocity (r = 0.38, P < 0.001), respectively (Fig. 3C). Flux and velocity differences were strongly correlated (r = 0.73, P < 0.001; Fig. 3C). Next, we compared the U46619-induced capillary diameter changes at pericyte bodies and halfway between them. The constrictions were found to be significantly more pronounced at pericyte bodies (median 83% vs. 96% of basal diameter, P < 0.0005, n = 19, Fig. 3D), indicating that they reflected changes in pericyte contractile tone. In dilating capillaries, diameter changes did not differ significantly between sites populated by pericyte bodies and halfway between them, although they tended to be larger at pericyte bodies (median 119% vs. 108% of basal, n = 6).

Fig. 3.
U46619 induces pericyte contraction in vivo, paralleled by RBC velocity and flux changes. (A) Capillary of the sensory cortex of anesthetized mouse, imaged before and after the application of 10 μM U46619. Plasma was labeled by TRITC-dextran (red). ...

U46619 did not have consistent effects on the diameters of arteries and arterioles at the pial surface. Five of 10 imaged arterioles (1 per animal) showed constrictions (75 ± 10% of baseline), 4 showed dilatations (130 ± 19% of baseline), and 1 artery did not visibly react. Nevertheless, we always measured a decrease in CBF by laser Doppler flowmetry (LDF) in response to U46619 (75 ± 8% of baseline, n = 9). This discrepancy, together with the heterogeneous capillary diameter response after U46619 administration, the correlation of capillary diameter and perfusion changes, and the enhanced constriction at pericyte bodies, suggests that pericytes in capillaries are effective regulators of blood flow.

Capillary Dilatation Is Not Required for Functional Hyperemia.

Next, we sought to elucidate whether similar localized capillary diameter changes, attributable to the activity of pericytes, were present during neuronal activity-induced hyperemia. We inserted a micropipette into the parietal cortex of mice, which was filled with 10 mM of the GABAA receptor antagonist, bicuculline (n = 8, Fig. 4G). Leakage of bicuculline from the micropipette tip led to sharp recurring bursts of neuronal spike activity (Fig. 4A and ref. 9). We categorized cortical vessels located within ~100 μm from the micropipette tip into pial, penetrating, precapillary arterioles or capillaries on the basis of topology, vessel wall morphology, diameter, and RBC velocity (Fig. 4 C and D). Precapillary arterioles and pericyte-containing capillaries were imaged at 150–300 μm depth in cortical layer II. The distributions of average diameter and RBC velocity differed significantly between all vessel types (Fig. 4 C and D), indicating that we had identified distinct vessel types. Diameter increases associated with neuronal activity occurred consistently in pial, penetrating, or precapillary arterioles, but not at pericytes in capillaries. Penetrating arterioles showed the most pronounced reactions. RBC velocity increases were detected in all vessel types. Fig. 4A and Movies S5, S6, S7, and S8 provide typical tracings of the diameter and RBC velocity responses. When averaged, diameter responses of pial, penetrating, and parenchymal arterioles peaked at 102.4 ± 3.3%, 103.4 ± 3.5%, and 102.3 ± 5% of preburst basal values, respectively. Capillary diameter responses reached only 100.1 ± 2.5% of prespike basal values, measured at pericytes at the time of maximal RBC velocity increase (Fig. 4B). No correlation was found between diameter and RBC velocity or between diameter and flux changes in capillaries (Fig. 4 E and F). None of the different vessel types showed significant differences in the time to rise or time to peak of the diameter or RBC velocity changes (Fig. S2). These results suggest that relaxation of pericytes in capillaries neither is required for nor substantially contributes to the development of the functional hyperemic response. Pial, penetrating, and precapillary arterioles were the effectors of flow changes during neurovascular coupling. Low-frequency oscillations (~0.1–0.2 Hz) of vessel diameter were observed in arterioles, but not in capillaries with pericytes (Fig. S3). Although the frequency would match vasomotor oscillations (10), which have been linked to fluctuations in the electrical and metabolic activity of the “resting” brain (11), the oscillations we observed in arterioles were clearly associated with periodic changes in the frequency of bicuculline-induced spiking bursts (Fig. S3). Incidentally, we observed one capillary in which a pericyte contraction led to a cessation of RBC flow irrespective of spike burst activity (Movie S9).

Fig. 4.
Capillary dilatation does not partake in the hyperemic response induced by bicuculline. (A) Original LFP, diameter, and RBC velocity traces of different vascular segments. The LFP traces (blue) show typical bicuculline-induced activity bursts. (Upper ...

Capillaries Dilate Passively During CSD.

To test whether a more prolonged vasodilatory stimulus is able to provoke responses at the level of capillaries, we induced CSD, a spreading wave of neuronal and glial depolarization associated with hyperemia. We elicited 15 CSDs in eight animals by electrical stimulation of the frontal cortex, while recording epidural electrocorticogram (ECoG), measuring LDF blood flow, and performing TPLSM imaging over the parietal cortex (Fig. 5A). Single tissue volumes of the parietal cortex containing precapillary arterioles and downstream capillaries were imaged. After electrical stimulation, the passage of CSD was detected by the typical transient decrease in spontaneous ECoG activity, negative direct current (DC)-potential shift, and increase in CBF (Fig. 5B). A dilatory response was observed in precapillary arterioles, which coincided with the dilatation of capillaries (Fig. 5C). Importantly, capillary dilatations occurred irrespective of the presence of pericyte bodies (median 124% of basal at pericyte bodies vs. 126% between pericyte bodies, n = 12, P = 0.33; Fig. 5D). These results suggest that capillaries dilate passively due to increased perfusion pressure during CSD-induced hyperemia. However, even under these conditions, localized constrictions of some capillaries were detected (Movie S10). The repeated finding of capillary constrictions throughout different experimental setups suggests that pericytes mediate local capillary vasoactivity in the CNS, albeit unrelated to neurovascular coupling.

Fig. 5.
Capillaries dilate passively during CSD. (A) Scheme of the preparation. A bipolar stimulation electrode placed over the frontal cortex is used to elicit CSDs. TPLSM imaging, ECoG/DC, and LDF recording are performed through a closed parietal window. ( ...


Pericytes are contractile cells that surround capillaries in the brain at high density. The traditional view that CBF is regulated solely by precapillary arterioles has recently been challenged by studies in retina and cerebellar slices (6), as well as in ischemic brain tissue (12). However, there is still no direct evidence that pericytes control CBF. In part, this may be due to the difficulties of visualizing CNS pericytes in vivo. Making use of GFP transgenic mice, we demonstrate in real time the contractile function of pericytes in brain capillaries and its effect on capillary flow. In experimental stroke, capillary constrictions obstruct RBC flow for hours despite successful reopening of the occluded vessel (12), suggesting that pericytes may be involved in the “no-reflow” phenomenon after cerebral ischemia. We asked whether TBXA2, a classical mediator of vasoconstriction, could affect pericyte tone and cause capillary flow disturbances. Topical administration of the TBXA2 receptor agonist U46619 caused constrictions of capillaries in vivo. Although the impact of U46619 on CBF measured by LDF was moderate (~25% decrease), tissue hypoperfusion may lead to edema of astrocyte end feet and compromise capillary patency independent of pericyte function (13). However, constrictions were more pronounced at pericyte bodies, indicating that they were caused by active pericyte contractility. Furthermore, we replicated U46619-induced pericyte contractions ex vivo in acute brain slices, where, in the absence of blood flow, tissue homeostasis is guaranteed by superfusion with oxygenated artificial (a)CSF. In vivo, RBC flow in capillaries is facilitated by the presence of a thin fluid layer between the RBC and the endothelium. Exhaustion of this layer by subtle decreases in capillary diameter might have a profound impact on resistance to RBC flow (14). In our study, RBC flow changes in single capillaries correlated with diameter changes. Thus, it seems likely that minor changes in capillary diameters, effected by pericyte contractility, could play a crucial role under pathological conditions of the brain, e.g., ischemia, where TBXA2 is produced endogenously (15).

One of the challenging questions remains whether pericytes also participate in neurovascular coupling, i.e., the process that links neural activity to local increases in blood flow. Dilatation of capillaries has recently been described during prolonged functional stimulation of the rat whisker barrel cortex in vivo (16). However, our CSD data implicate that capillaries may dilate passively in response to increased perfusion pressure from upstream arteriolar dilatation. Thus, it would appear that direct visualization of pericyte function in vivo is mandatory to address their role in neurovascular coupling. Because vasodilatation propagates to feeding vessels during functional hyperemia (17, 18), we speculated that short hyperemic stimuli could prevent the recruitment of larger vessels and unveil the relaxation of pericytes in capillaries. Unfortunately, we were unable to obtain reproducible and stable hemodynamic responses to repeated, 15-s whisker stimulations in anesthetized mice, which would have allowed for sequential acquisition of diameter and perfusion changes in different segments of the vascular tree. To overcome this obstacle, we used focal application of bicuculline, an inhibitor of GABAA receptors that induces synchronized neuronal depolarizations of brief duration (~100 ms) and high metabolic demand (9). In our experiments, the RBC velocity changes in response to bicuculline were smaller than those previously reported during somatosensory or olfactory stimulation (19, 20). Nevertheless, we did observe a functional hyperemic response with dilatation of precapillary, penetrating, and pial arterioles. In contrast, pericytes in capillaries showed no changes.

Although the domains of pial or penetrating arterioles do not match the boundaries of neuronal functional columns in the somatosensory cortex, neuronal columns exhibit localized hyperemic responses, at least during the initial seconds after stimulation (21). Thus, daughter vessels must allocate the blood flow increase to the activated neural parenchyma. Our data support the notion that precapillary arterioles carry out this function (22). We find no evidence for neurovascular coupling at the level of capillaries, as was hypothesized on the basis of ex vivo findings (6). Hence, the distribution of precapillary arterioles limits the spatial resolution of the functional hyperemic response, which is the basis of brain functional imaging techniques like fMRI or PET.

It could be argued that GABAergic inhibition by bicuculline may have interfered with pericyte function in our experiments. GABAergic signaling has been shown to influence the tone of cortical vessels ex vivo and mediates the cortical hyperemia induced by stimulation of the basal forebrain (23, 24). In fact, GABAergic terminals arising from local interneurons innervate the cortical parenchymal microvasculature, including arterioles and capillaries (25). However, precapillary arterioles, which were only slightly wider than capillaries (but functionally distinct, as demonstrated by their arteriolar RBC velocity, see ref. 26), were able to dilate in the presence of bicuculline. Further, whereas cerebellar pericytes are indeed contacted by GABAergic terminals (27), inhibition of GABAergic signaling by bicuculline in the cerebellum does not affect basal blood flow or neuronal activity-induced functional blood flow responses (28, 29).

In summary, we performed real-time imaging of pericytes in the cerebral cortex of anesthetized mice to evaluate their contribution to blood flow control in vivo. Our findings suggest that pericytes can modulate CBF under pathological conditions, which may have important implications for CNS disorders. In contrast, we find no evidence for neurovascular coupling by capillary pericytes in the mouse brain.


Detailed methods are provided in SI Methods.


We used heterozygous adult β-actin-GFP transgenic mice of either sex (7) bred in our facilities. All animal procedures were performed in accordance with the standards for animal care of our institution and permission was obtained according to the national regulations.

TPLSM Vessel Imaging and Analysis.

Two-photon images (either stacks or single focal planes) from GFP-positive vessels were acquired using a Leica TCS SP2 microscope. Outer diameters were measured manually using ImageJ (Wayne Rasband, US National Institutes of Health, Bethesda) or automatically using custom written MATLAB software (MathWorks). RBC velocity and flux measurements were performed as described previously (30, 31). In the U46619 experiments, the capillary diameter was measured at the points of maximal constriction/dilatation. Separately, diameter changes at pericyte bodies or at capillaries halfway between two neighboring pericytes were assessed. In the bicuculline experiments, one single focal plane of the vessel under study was imaged, and diameter was measured in segments populated by SMCs or pericytes. In the CSD experiments, diameter measurements were undertaken at SMCs in arterioles and, in capillaries, at segments either populated by pericyte bodies or halfway between them.

Acute Brain Slice Experiments.

Coronal sections (300 μm thick) of the sensory cortex were cut and placed in artificial cerebrospinal fluid bubbled with carbogen. We imaged capillaries running parallel to the slice surface at 70–100 μm depth. U46619 or SQ 29,548 (Cayman Chemical) was dissolved in aCSF.

In Vivo Experiments.

Throughout imaging, thiopental-anesthetized mice (initial dosage 75 mg/kg body weight i.v.) were mechanically ventilated and physiological parameters were monitored. All mice received 100 μL of 5% TRITC-dextran (molecular mass 70,000 kDa, wt/vol) in saline to label blood plasma. In the U46619 in vivo experiments, the drug (10 μM) or vehicle was superfused through a closed cranial window, and tissue volumes containing the vessel were scanned. CBF was monitored with a LDF probe over the exposed cortex. In the bicuculline experiments, the drug (10 mM) leaked from the tip of a micropipette inserted in the cortex, which served as a local field potential (LFP)-recording electrode. Vessels were imaged at a single focal plane at a frequency of ~0.5–0.8 Hz. Isolated activity bursts (separated from the previous and the next by at least 2 s) were detected off-line and the diameter or velocity responses pooled and averaged. For the CSD experiments, an additional open cranial window was prepared over the frontal cortex. A bipolar electrode was placed over the exposed dura at the frontal window, and a train of five current pulses (1 mA, 100 ms, 1 Hz) was delivered to provoke CSD. An epidural electrode in the imaging window recorded the DC potential and ECoG. CBF was recorded simultaneously by LDF. Tissue volumes containing precapillary arterioles and their downstream capillaries were imaged at 1-min lapses for assessment of vessel diameter changes.

Statistical Analysis.

Unless otherwise stated, data are presented as means ± SD. Where tested distributions were not distinct from normal, Student's t test, one-way ANOVA, or one-way ANOVA for repeated measurements with Bonferroni correction was used. Otherwise, the Mann–Whitney–Wilcoxon or the Wilcoxon signed ranks test was chosen.

Supplementary Material

Supporting Information:


We thank G. Royl for his help with the automated capillary flow measurement routine and Jörg Rösner for his excellent support at the TPLSM facility. We also thank C. Schaffer and N. Nishimura for kindly making their software available. This work was supported by the Deutsche Forschungsgemeinschaft, the Bundesministerium für Bildung und Forschung, and the Hermann and Lilly Schilling Foundation.


The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1011321108/-/DCSupplemental.


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