Precapillary sphincters and pericytes at first-order capillaries as key regulators for brain capillary perfusion

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Rises in local neural activity trigger local increases of cerebral blood flow, which is essential to match local energy demands. However, the specific location of microvascular flow control is incompletely understood. Here, we used two-photon microscopy to observe brain microvasculature in vivo. Small spatial movement of a threedimensional (3D) vasculature makes it challenging to precisely measure vessel diameter at a single x-y plane. To overcome this problem, we carried out four-dimensional (x-y-z-t) imaging of brain microvessels during exposure to vasoactive molecules in order to constrain the impact of brain movements on the recordings. We demonstrate that rises in synaptic activity, acetylcholine, nitric oxide, cyclic guanosine monophosphate, ATP-sensitive potassium channels, and endothelin-1 exert far greater effects on brain precapillary sphincters and first-order capillaries than on penetrating arterioles or downstream capillaries, but with similar kinetics. The high level of responsiveness at precapillary sphincters and first-order capillaries was matched by a higher level of α-smooth muscle actin in pericytes as compared to penetrating arterioles and downstream capillaries. Mathematical modeling based on 3D vasculature reconstruction showed that precapillary sphincters predominantly regulate capillary blood flow and pressure as compared to penetrating arterioles and downstream capillaries. Our results confirm a key role for precapillary sphincters and pericytes on first-order capillaries as sensors and effectors of endothelium- or brain-derived vascular signals.

Original languageEnglish
Article numbere2023749118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number26
Publication statusPublished - 2021

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. We acknowledge Dr. Søren Grubb, Dr. Krzysztof Kucharz, Dr. Henrik Flyvbjerg, Dr. Barbara Lind, and Dr. Nikolay Kutuzov for scientific discussions. We also acknowledge Dr. Søren Grubb for providing the z-stack for our modeling work. We acknowledge the Core Facility for Integrated Microscopy, Faculty of Health and Medical Sciences, University of Copenhagen, where we used confocal and spinning disc confocal microscopy in our in vitro studies. We further acknowledge Dr. Thor Møller for introduction to and assistance with the IP-one assay. This study was supported by the Lundbeck Foundation, the Danish Medical Research Council, the Alice Brenaa Foundation, Augustinus Foundation, Carl og Ellen Hertz Familiele-gat, the NOVO Nordisk Foundation, and a Nordea Foundation grant to the Center for Healthy Aging.

Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.

    Research areas

  • Arterioles, Capillaries, Neurovascular coupling (NVC), Pericytes, Vascular smooth muscle

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