TY - JOUR
T1 - Perivascular clearance of blood proteins after blood-brain barrier disruption in a rat model of microinfarcts
AU - Georgakopoulou, Theodosia
AU - van der Wijk, Anne-Eva
AU - van Bavel, Ed
AU - Bakker, Erik N. T. P.
N1 - Funding Information: This project was funded by the European Union 's Horizon 2020 research and innovation program under grant agreement No 777072 (INSIST) and Neuroscience Amsterdam (project number NDIS-2019-03 ). Funding Information: This project was funded by the European Union's Horizon 2020 research and innovation program under grant agreement No 777072 (INSIST) and Neuroscience Amsterdam (project number NDIS-2019-03). Publisher Copyright: © 2023 The Authors
PY - 2023/7/1
Y1 - 2023/7/1
N2 - Microinfarcts result in a transient loss of the blood-brain barrier (BBB) in the ischemic territory. This leads to the extravasation of blood proteins into the brain parenchyma. It is not clear how these proteins are removed. Here we studied the role of perivascular spaces in brain clearance from extravasated blood proteins. Male and female Wistar rats were infused with microspheres of either 15, 25, or 50 μm in diameter (n = 6 rats per group) via the left carotid artery. We infused either 25,000 microspheres of 15 μm, 5500 of 25 μm, or 1000 of 50 μm. One day later, rats were infused with lectin and hypoxyprobe to label perfused blood vessels and hypoxic areas, respectively. Rats were then euthanized and perfusion-fixed. Brains were excised, sectioned, and analyzed using immunostaining and confocal imaging. Microspheres induced a size-dependent increase in ischemic volume per territory, but the cumulative ischemic volume was similar in all groups. The total volumes of ischemia, hypoxia and infarction affected 1–2 % of the left hemisphere. Immunoglobulins (IgG) were present in ischemic brain tissue surrounding lodged microspheres in all groups. In addition, staining for IgG was found in perivascular spaces of blood vessels nearby areas of BBB disruption. About 2/3 of these vessels were arteries, while the remaining 1/3 of these vessels were veins. The subarachnoid space (SAS) of the affected hemisphere stained stronger for IgG than the contralateral hemisphere in all groups: +27 %, +44 % and +27 % respectively. Microspheres of various sizes induce a local loss of BBB integrity, evidenced by parenchymal IgG staining. The presence of IgG in perivascular spaces of both arteries and veins distinct from the ischemic territories suggests that both contribute to the removal of blood proteins. The strong staining for IgG in the SAS of the affected hemisphere suggests that this perivascular route egresses via the CSF. Perivascular spaces therefore play a previously unrecognized role in tissue clearance of fluid and extravasated proteins after BBB disruption induced by microinfarcts.
AB - Microinfarcts result in a transient loss of the blood-brain barrier (BBB) in the ischemic territory. This leads to the extravasation of blood proteins into the brain parenchyma. It is not clear how these proteins are removed. Here we studied the role of perivascular spaces in brain clearance from extravasated blood proteins. Male and female Wistar rats were infused with microspheres of either 15, 25, or 50 μm in diameter (n = 6 rats per group) via the left carotid artery. We infused either 25,000 microspheres of 15 μm, 5500 of 25 μm, or 1000 of 50 μm. One day later, rats were infused with lectin and hypoxyprobe to label perfused blood vessels and hypoxic areas, respectively. Rats were then euthanized and perfusion-fixed. Brains were excised, sectioned, and analyzed using immunostaining and confocal imaging. Microspheres induced a size-dependent increase in ischemic volume per territory, but the cumulative ischemic volume was similar in all groups. The total volumes of ischemia, hypoxia and infarction affected 1–2 % of the left hemisphere. Immunoglobulins (IgG) were present in ischemic brain tissue surrounding lodged microspheres in all groups. In addition, staining for IgG was found in perivascular spaces of blood vessels nearby areas of BBB disruption. About 2/3 of these vessels were arteries, while the remaining 1/3 of these vessels were veins. The subarachnoid space (SAS) of the affected hemisphere stained stronger for IgG than the contralateral hemisphere in all groups: +27 %, +44 % and +27 % respectively. Microspheres of various sizes induce a local loss of BBB integrity, evidenced by parenchymal IgG staining. The presence of IgG in perivascular spaces of both arteries and veins distinct from the ischemic territories suggests that both contribute to the removal of blood proteins. The strong staining for IgG in the SAS of the affected hemisphere suggests that this perivascular route egresses via the CSF. Perivascular spaces therefore play a previously unrecognized role in tissue clearance of fluid and extravasated proteins after BBB disruption induced by microinfarcts.
KW - Animal model
KW - Blood-brain barrier
KW - Glymphatics
KW - Microinfarcts
UR - http://www.scopus.com/inward/record.url?scp=85149450493&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.mvr.2023.104515
DO - https://doi.org/10.1016/j.mvr.2023.104515
M3 - Article
C2 - 36893583
SN - 0026-2862
VL - 148
JO - Microvascular Research
JF - Microvascular Research
M1 - 104515
ER -