Brain capillary pericytes exert a substantial but slow influence on blood flow

Abstract

The majority of the brain’s vasculature is composed of intricate capillary networks lined by capillary pericytes. However, it remains unclear whether capillary pericytes influence blood flow. Using two-photon microscopy to observe and manipulate brain capillary pericytes in vivo, we find that their optogenetic stimulation decreases lumen diameter and blood flow, but with slower kinetics than similar stimulation of mural cells on upstream pial and precapillary arterioles. This slow vasoconstriction was inhibited by the clinically used vasodilator fasudil, a Rho-kinase inhibitor that blocks contractile machinery. Capillary pericytes were also slower to constrict back to baseline following hypercapnia-induced dilation, and slower to dilate towards baseline following optogenetically induced vasoconstriction. Optical ablation of single capillary pericytes led to sustained local dilation and a doubling of blood cell flux selectively in capillaries lacking pericyte contact. These data indicate that capillary pericytes contribute to basal blood flow resistance and slow modulation of blood flow throughout the brain.

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Fig. 1: Capillary pericytes contact the vast majority of mouse cerebrovasculature.
Fig. 2: Optogenetic activation of capillary pericytes constricts capillaries and reduces blood flow.
Fig. 3: Topical administration of fasudil prevents hemodynamic changes induced by optogenetic stimulation of capillary pericytes.
Fig. 4: Distinct contractile dynamics of mural cells in different microvascular zones.
Fig. 5: Dilation after optogenetic vasoconstriction is faster in precapillary arterioles than capillaries.
Fig. 6: Ablation of individual capillary pericytes produces local capillary dilation and increased RBC flux.
Fig. 7: Pericytes control heterogeneity of basal capillary vasodynamics.

Data availability

Source data are provided with this paper. Any additional data are available from the corresponding author upon request.

Code availability

Vasometrics54, an ImageJ/Fiji-based macro for unbiased vessel diameter measurement, can be downloaded at: https://github.com/mcdowellkonnor/ResearchMacros. All other code is available from the corresponding author upon request.

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Acknowledgements

Our work is supported by grants to A.Y.S. from the NIH/NINDS (grant nos. NS106138, NS097775) and the NIH/NIA (AG063031, AG062738), by the American Heart Association (grant no. 14GRNT20480366), by the Alzheimer’s Association NIRG award (grant no. 2016-NIRG-397149) and by an Institutional Development Award (IDeA) from the NIGMS under grant no. P20GM109040. D.A.H. is supported by awards from the NIH/NCATS (grant nos. UL1 TR001450 and TL1 TR001451) and by NIH/NINDS grant no. F30NS096868. We thank J. Costello for contributions to image analysis. We appreciate the helpful comments and discussion of M. Levy, D. Kleinfeld, A. Riegel, P. Kara and N. Bhat.

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Experiments were designed by A.Y.S., D.A.H. and A.-A.B. Experiments were conducted by D.A.H., A.-A.B., R.I.G., S.A.H., T.K. and A.Y.S. Data analysis was performed by D.A.H., A.-A.B., S.A.H., T.K., T.T., K.P.M. and A.Y.S. Statistics were performed by A.L.K., A.V.F. and D.A.H. The manuscript was written by A.Y.S. and D.A.H. with contributions from all authors.

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Correspondence to Andy Y. Shih.

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Peer review information Nature Neuroscience thanks David Bennett, Turgay Dalkara and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–24.

Reporting Summary

Supplementary Video 1

Line-scan data from ChR2-YFP mouse.

Supplementary Video 2

Line-scan data from YFP control mouse.

Supplementary Video 3

Hypercapnia-induced dilation of pre-capillary arterioles and capillaries.

Supplementary Video 4

Optogenetically induced constriction of pre-capillary arteriole followed by relaxation.

Supplementary Video 5

Optogenetically induced constriction of pre-capillary arteriole followed by relaxation (second example).

Supplementary Video 6

Optogenetically induced constriction of capillary followed by relaxation.

Supplementary Video 7

Optogenetically induced constriction of capillary followed by relaxation (second example).

Supplementary Video 8

Absence of precapillary arteriole constriction in YFP control mouse.

Supplementary Video 9

Absence of capillary constriction in YFP control mouse.

Supplementary Data 1

All data used to generate plots in the supplementary files and associated statistical analyses.

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Source Data Fig. 5

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Source Data Fig. 7

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Hartmann, D.A., Berthiaume, AA., Grant, R.I. et al. Brain capillary pericytes exert a substantial but slow influence on blood flow. Nat Neurosci (2021). https://doi.org/10.1038/s41593-020-00793-2

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