TY - JOUR

T1 - Precapillary sphincters and pericytes at first-order capillaries as key regulators for brain capillary perfusion

AU - Zambach, Stefan Andreas

AU - Cai, Changsi

AU - Helms, Hans Christian Cederberg

AU - Hald, Bjørn Olav

AU - Dong, Yiqiu

AU - Fordsmann, Jonas Christoffer

AU - Nielsen, Reena Murmu

AU - Hu, Jingshi

AU - Lønstrup, Micael

AU - Brodin, Birger

AU - Lauritzen, Martin Johannes

N1 - 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.

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - Arterioles

KW - Capillaries

KW - Neurovascular coupling (NVC)

KW - Pericytes

KW - Vascular smooth muscle

U2 - 10.1073/pnas.2023749118

DO - 10.1073/pnas.2023749118

M3 - Journal article

C2 - 34155102

AN - SCOPUS:85108339896

VL - 118

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 26

M1 - e2023749118

ER -