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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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.
The authors declare no competing interests.
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.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Figs. 1–24.
Line-scan data from ChR2-YFP mouse.
Line-scan data from YFP control mouse.
Hypercapnia-induced dilation of pre-capillary arterioles and capillaries.
Optogenetically induced constriction of pre-capillary arteriole followed by relaxation.
Optogenetically induced constriction of pre-capillary arteriole followed by relaxation (second example).
Optogenetically induced constriction of capillary followed by relaxation.
Optogenetically induced constriction of capillary followed by relaxation (second example).
Absence of precapillary arteriole constriction in YFP control mouse.
Absence of capillary constriction in YFP control mouse.
All data used to generate plots in the supplementary files and associated statistical analyses.
Source data for Fig. 1.
Source data and statistical details for Fig. 2.
Source data and statistical details for Fig. 3.
Source data and statistical details for Fig. 4.
Source data and statistical details for Fig. 5.
Source data and statistical details for Fig. 6.
Source data and statistical details for 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