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Functions of Pericytes in Ischemic Stroke

Roth, Michaela LU (2019) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2019(99).
Abstract
Ischemic stroke remains one of the leading causes of death and disability worldwide, and its burden is predicted to further increase due to the aging population. The only available treatments, thrombolysis or thrombectomy, can only be applied within a limited time window after stroke onset, and thus are applicable only to a small proportion of stroke patients. Therefore, there is an increasing need for new therapeutic approaches. In addition to neuronal cell death, the stroke pathology is characterized by the breakdown of the blood-brain barrier (BBB), resulting in the accumulation of blood-derived components within the brain, further aggravating neuronal cell death. Several repair mechanisms occur within the brain after the ischemic... (More)
Ischemic stroke remains one of the leading causes of death and disability worldwide, and its burden is predicted to further increase due to the aging population. The only available treatments, thrombolysis or thrombectomy, can only be applied within a limited time window after stroke onset, and thus are applicable only to a small proportion of stroke patients. Therefore, there is an increasing need for new therapeutic approaches. In addition to neuronal cell death, the stroke pathology is characterized by the breakdown of the blood-brain barrier (BBB), resulting in the accumulation of blood-derived components within the brain, further aggravating neuronal cell death. Several repair mechanisms occur within the brain after the ischemic insult, including vascular remodeling to reestablish the blood flow as well as scar formation to both replace the injured tissue and contain the inflammation within the injured ischemic core.

Pericytes, perivascular cells lining capillaries, have increasingly gained interest as a novel target cell type. This is due to their multiple functions after stroke that include maintenance of the BBB and their participation in vascular remodeling and scar formation. Pericytes undergo several morphological and phenotypic changes in stroke. One of these changes is the expression of Regulator of G-protein signaling 5 (RGS5), a protein that is upregulated in pericytes after stroke before they detach from the vessels, suggesting its involvement in this detachment process. However, the time course of the pericyte response in relation to other vascular changes, and the impact that loss of RGS5 has on pericytes and their function during the different stages of stroke are not yet known.

Using a permanent stroke model in mice, we established the temporal sequence of the pericyte response in relation to other vascular events after ischemic stroke. Pericytes were the first vascular cells to respond to ischemic stroke by either undergoing cell death or activation. Most importantly, the pericyte response preceded loss of tight junction (TJ) proteins, endothelial cell death and BBB leakage. Loss of RGS5 in pericytes resulted in increased pericyte numbers and coverage. In the acute phase, the increased pericyte coverage in RGS5-knock out (KO) mice prevented TJ loss and reduced the BBB breakdown. This was associated with a reduction in neuronal cell death after stroke. In the chronic phase, loss of RGS5 reduced detachment of platelet-derived growth factor receptor ß (PDGFRß)+ pericytes from the vascular wall, resulting in a shift from a parenchymal to a perivascular location of PDGFRß+ cells. This was accompanied by maintenance of PDGFRß-signaling at baseline levels and vessel stabilization as seen by increased vascular density and reduced vascular leakage. Pericytes that migrate into the parenchyma following stroke have been suggested to be involved in scar formation after stroke. However, a reduction in parenchymal PDGFRß+ cells by 50% in RGS5-KO mice did not lead to alterations in the deposition of the extracellular matrix proteins type I collagen and fibronectin; however, it resulted in an earlier maturation of the glial scar.

In conclusion, the results in this thesis identify pericytes as an early responder after stroke. Our studies highlight RGS5 as an important modulator of neurovascular protection in the acute phase and vascular remodeling in the chronic phase after stroke. Targeting pericytes, for example via RGS5, constitutes a potential novel target for therapeutic interventions.
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author
supervisor
opponent
  • Professor Lauritzen, Martin, Department of Neuroscience, University of Copenhagen
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Stroke, Pericytes, RGS5, Blood-brain barrier, vascular remodelling, scar formation
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2019
issue
99
pages
86 pages
publisher
Lund University: Faculty of Medicine
defense location
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund
defense date
2019-10-25 09:00:00
ISSN
1652-8220
ISBN
978-91-7619-828-5
language
English
LU publication?
yes
id
65fceba5-2a20-4500-9d3b-8211a96e6788
date added to LUP
2019-09-18 08:40:20
date last changed
2020-09-17 09:02:16
@phdthesis{65fceba5-2a20-4500-9d3b-8211a96e6788,
  abstract     = {{Ischemic stroke remains one of the leading causes of death and disability worldwide, and its burden is predicted to further increase due to the aging population. The only available treatments, thrombolysis or thrombectomy, can only be applied within a limited time window after stroke onset, and thus are applicable only to a small proportion of stroke patients. Therefore, there is an increasing need for new therapeutic approaches. In addition to neuronal cell death, the stroke pathology is characterized by the breakdown of the blood-brain barrier (BBB), resulting in the accumulation of blood-derived components within the brain, further aggravating neuronal cell death. Several repair mechanisms occur within the brain after the ischemic insult, including vascular remodeling to reestablish the blood flow as well as scar formation to both replace the injured tissue and contain the inflammation within the injured ischemic core. <br/><br/>Pericytes, perivascular cells lining capillaries, have increasingly gained interest as a novel target cell type. This is due to their multiple functions after stroke that include maintenance of the BBB and their participation in vascular remodeling and scar formation. Pericytes undergo several morphological and phenotypic changes in stroke. One of these changes is the expression of Regulator of G-protein signaling 5 (RGS5), a protein that is upregulated in pericytes after stroke before they detach from the vessels, suggesting its involvement in this detachment process. However, the time course of the pericyte response in relation to other vascular changes, and the impact that loss of RGS5 has on pericytes and their function during the different stages of stroke are not yet known.<br/><br/>Using a permanent stroke model in mice, we established the temporal sequence of the pericyte response in relation to other vascular events after ischemic stroke. Pericytes were the first vascular cells to respond to ischemic stroke by either undergoing cell death or activation. Most importantly, the pericyte response preceded loss of tight junction (TJ) proteins, endothelial cell death and BBB leakage. Loss of RGS5 in pericytes resulted in increased pericyte numbers and coverage. In the acute phase, the increased pericyte coverage in RGS5-knock out (KO) mice prevented TJ loss and reduced the BBB breakdown. This was associated with a reduction in neuronal cell death after stroke. In the chronic phase, loss of RGS5 reduced detachment of platelet-derived growth factor receptor ß (PDGFRß)+ pericytes from the vascular wall, resulting in a shift from a parenchymal to a perivascular location of PDGFRß+ cells. This was accompanied by maintenance of PDGFRß-signaling at baseline levels and vessel stabilization as seen by increased vascular density and reduced vascular leakage. Pericytes that migrate into the parenchyma following stroke have been suggested to be involved in scar formation after stroke. However, a reduction in parenchymal PDGFRß+ cells by 50% in RGS5-KO mice did not lead to alterations in the deposition of the extracellular matrix proteins type I collagen and fibronectin; however, it resulted in an earlier maturation of the glial scar. <br/><br/>In conclusion, the results in this thesis identify pericytes as an early responder after stroke. Our studies highlight RGS5 as an important modulator of neurovascular protection in the acute phase and vascular remodeling in the chronic phase after stroke. Targeting pericytes, for example via RGS5, constitutes a potential novel target for therapeutic interventions.<br/>}},
  author       = {{Roth, Michaela}},
  isbn         = {{978-91-7619-828-5}},
  issn         = {{1652-8220}},
  keywords     = {{Stroke; Pericytes; RGS5; Blood-brain barrier; vascular remodelling; scar formation}},
  language     = {{eng}},
  number       = {{99}},
  publisher    = {{Lund University: Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Functions of Pericytes in Ischemic Stroke}},
  url          = {{https://lup.lub.lu.se/search/files/69642437/e_nailing_Roth.pdf}},
  volume       = {{2019}},
  year         = {{2019}},
}