3K3A-Activated Protein C Protects the Blood-Brain Barrier and Neurons From Accelerated Ischemic Injury Caused by Pericyte Deficiency in Mice
Pericytes, mural cells of brain capillaries, maintain the blood-brain barrier (BBB), regulate cerebral blood flow (CBF), and protect neurons against ischemic damage. To further investigate the role of pericytes in ischemia, we induced stroke by 45-min transient middle cerebral artery occlusion (tMCA...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-03-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2022.841916/full |
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| author | Yaoming Wang Kassandra Kisler Angeliki Maria Nikolakopoulou Jose A. Fernandez John H. Griffin John H. Griffin Berislav V. Zlokovic |
| author_facet | Yaoming Wang Kassandra Kisler Angeliki Maria Nikolakopoulou Jose A. Fernandez John H. Griffin John H. Griffin Berislav V. Zlokovic |
| author_sort | Yaoming Wang |
| collection | DOAJ |
| description | Pericytes, mural cells of brain capillaries, maintain the blood-brain barrier (BBB), regulate cerebral blood flow (CBF), and protect neurons against ischemic damage. To further investigate the role of pericytes in ischemia, we induced stroke by 45-min transient middle cerebral artery occlusion (tMCAo) in 6-month-old pericyte-deficient Pdgfrb + /− mice and control Pdgfrb+/+ littermates. Compared to controls, Pdgfrb + /− mice showed a 26% greater loss of CBF during early reperfusion, and 40–50% increase in the infarct and edema volumes and motor neurological score 24 h after tMCAo. These changes were accompanied by 50% increase in both immunoglobulin G and fibrinogen pericapillary deposits in the ischemic cortex 8 h after tMCAo indicating an accelerated BBB breakdown, and 35 and 55% greater losses of pericyte coverage and number of degenerating neurons 24 h after tMCAo, respectively. Treatment of Pdgfrb + /− mice with 3K3A-activated protein C (APC), a cell-signaling analog of plasma protease APC, administered intravenously 10 min and 4 h after tMCAo normalized CBF during the early reperfusion phase and reduced infarct and edema volume and motor neurological score by 55–60%, with similar reductions in BBB breakdown and number of degenerating neurons. Our data suggest that pericyte deficiency results in greater brain injury, BBB breakdown, and neuronal degeneration in stroked mice and that 3K3A-APC protects the brain from accelerated injury caused by pericyte deficiency. These findings may have implications for treatment of ischemic brain injury in neurological conditions associated with pericyte loss such as those seen during normal aging and in neurodegenerative disorders such as Alzheimer’s disease. |
| first_indexed | 2024-12-22T16:31:12Z |
| format | Article |
| id | doaj.art-fee37c5c24b34d5b86b090f53605b805 |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-22T16:31:12Z |
| publishDate | 2022-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-fee37c5c24b34d5b86b090f53605b8052022-12-21T18:20:04ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2022-03-011610.3389/fnins.2022.8419168419163K3A-Activated Protein C Protects the Blood-Brain Barrier and Neurons From Accelerated Ischemic Injury Caused by Pericyte Deficiency in MiceYaoming Wang0Kassandra Kisler1Angeliki Maria Nikolakopoulou2Jose A. Fernandez3John H. Griffin4John H. Griffin5Berislav V. Zlokovic6Department of Physiology and Neuroscience, Keck School of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, United StatesDepartment of Physiology and Neuroscience, Keck School of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, United StatesDepartment of Physiology and Neuroscience, Keck School of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, United StatesDepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, United StatesDepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, United StatesDivision of Hematology/Oncology, Department of Medicine, University of California, San Diego, San Diego, CA, United StatesDepartment of Physiology and Neuroscience, Keck School of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, United StatesPericytes, mural cells of brain capillaries, maintain the blood-brain barrier (BBB), regulate cerebral blood flow (CBF), and protect neurons against ischemic damage. To further investigate the role of pericytes in ischemia, we induced stroke by 45-min transient middle cerebral artery occlusion (tMCAo) in 6-month-old pericyte-deficient Pdgfrb + /− mice and control Pdgfrb+/+ littermates. Compared to controls, Pdgfrb + /− mice showed a 26% greater loss of CBF during early reperfusion, and 40–50% increase in the infarct and edema volumes and motor neurological score 24 h after tMCAo. These changes were accompanied by 50% increase in both immunoglobulin G and fibrinogen pericapillary deposits in the ischemic cortex 8 h after tMCAo indicating an accelerated BBB breakdown, and 35 and 55% greater losses of pericyte coverage and number of degenerating neurons 24 h after tMCAo, respectively. Treatment of Pdgfrb + /− mice with 3K3A-activated protein C (APC), a cell-signaling analog of plasma protease APC, administered intravenously 10 min and 4 h after tMCAo normalized CBF during the early reperfusion phase and reduced infarct and edema volume and motor neurological score by 55–60%, with similar reductions in BBB breakdown and number of degenerating neurons. Our data suggest that pericyte deficiency results in greater brain injury, BBB breakdown, and neuronal degeneration in stroked mice and that 3K3A-APC protects the brain from accelerated injury caused by pericyte deficiency. These findings may have implications for treatment of ischemic brain injury in neurological conditions associated with pericyte loss such as those seen during normal aging and in neurodegenerative disorders such as Alzheimer’s disease.https://www.frontiersin.org/articles/10.3389/fnins.2022.841916/fullpericyteischemic strokeblood-brain barrierneuronsactivated protein C |
| spellingShingle | Yaoming Wang Kassandra Kisler Angeliki Maria Nikolakopoulou Jose A. Fernandez John H. Griffin John H. Griffin Berislav V. Zlokovic 3K3A-Activated Protein C Protects the Blood-Brain Barrier and Neurons From Accelerated Ischemic Injury Caused by Pericyte Deficiency in Mice Frontiers in Neuroscience pericyte ischemic stroke blood-brain barrier neurons activated protein C |
| title | 3K3A-Activated Protein C Protects the Blood-Brain Barrier and Neurons From Accelerated Ischemic Injury Caused by Pericyte Deficiency in Mice |
| title_full | 3K3A-Activated Protein C Protects the Blood-Brain Barrier and Neurons From Accelerated Ischemic Injury Caused by Pericyte Deficiency in Mice |
| title_fullStr | 3K3A-Activated Protein C Protects the Blood-Brain Barrier and Neurons From Accelerated Ischemic Injury Caused by Pericyte Deficiency in Mice |
| title_full_unstemmed | 3K3A-Activated Protein C Protects the Blood-Brain Barrier and Neurons From Accelerated Ischemic Injury Caused by Pericyte Deficiency in Mice |
| title_short | 3K3A-Activated Protein C Protects the Blood-Brain Barrier and Neurons From Accelerated Ischemic Injury Caused by Pericyte Deficiency in Mice |
| title_sort | 3k3a activated protein c protects the blood brain barrier and neurons from accelerated ischemic injury caused by pericyte deficiency in mice |
| topic | pericyte ischemic stroke blood-brain barrier neurons activated protein C |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2022.841916/full |
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