Functions of Pericytes in Ischemic Stroke
Författare
Summary, in English
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.
Avdelning/ar
Publiceringsår
2019
Språk
Engelska
Publikation/Tidskrift/Serie
Lund University, Faculty of Medicine Doctoral Dissertation Series
Volym
2019
Issue
99
Fulltext
- Available as PDF - 11 MB
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Dokumenttyp
Doktorsavhandling
Förlag
Lund University: Faculty of Medicine
Ämne
- Neurosciences
Nyckelord
- Stroke
- Pericytes
- RGS5
- Blood-brain barrier
- vascular remodelling
- scar formation
Status
Published
Forskningsgrupp
- Translational Neurology (TNY)
Handledare
ISBN/ISSN/Övrigt
- ISSN: 1652-8220
- ISBN: 978-91-7619-828-5
Försvarsdatum
25 oktober 2019
Försvarstid
09:00
Försvarsplats
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund
Opponent
- Martin Lauritzen (Professor)