Regulator of G‐protein signaling 5 regulates the shift from perivascular to parenchymal pericytes in the chronic phase after stroke

Abstract

Poststroke recovery requires multiple repair mechanisms, including vascular remodeling and blood‐brain barrier (BBB) restoration. Brain pericytes are essential for BBB repair and angiogenesis after stroke, but they also give rise to scar‐forming platelet‐derived growth factor receptor β (PDGFR‐β)‐expressing cells. However, many of the molecular mechanisms underlying this pericyte response after stroke still remain unknown. Regulator of G‐protein signaling 5 (RGS5) has been associated with pericyte detachment from the vascular wall, but whether it regulates pericyte function and vascular stabilization in the chronic phase of stroke is not known. Using RGS5‐knockout (KO) mice, we study how loss of RGS5 affects the pericyte response and vascular remodeling in a stroke model at 7 d after ischemia. Loss of RGS5 leads to a shift toward an increase in the number of perivascular pericytes and reduction in the density of parenchymal PDGFR‐β‐expressing cells associated with normalized PDGFR‐β activation after stroke. The redistribution of pericytes resulted in higher pericyte coverage, increased vascular density, preservation of vessel lengths, and a significant reduction in vascular leakage in RGS5‐KO mice compared with controls. Our study demonstrates RGS5 in pericytes as an important target to enhance vascular remodeling.—Roth, M., Gaceb, A., Enström, A., Padel, T., Genové, G., Özen, I., Paul, G. Regulator of G‐protein signaling 5 regulates the shift from perivascular to parenchymal pericytes in the chronic phase after stroke. FASEB J. 33, 8990–8998 (2019). http://www.fasebj.org

Parenchymal pericytes are not the major contributor of extracellular matrix in the fibrotic scar after stroke in male mice

“…Cell numbers are presented as per mm 2 . Parenchymal and perivascular PDGFRß + cells were distinguished by their morphology and location in relation to capillaries (Roth et al, ) (illustrated in Figure c). PDGFRß + cells with a clear cell soma and processes around capillaries were classified as perivascular PDGFRß + cells, while PDGFRß + cells located distant from the vessel with an amoeboid‐like morphology and multipolar irregular cell projections were classified as parenchymal PDGFRß + cells (Reeves et al, ).…”

“…Data are reported as mean ± SD , 95% confidence interval (CI) and illustrated in box and whiskers plots. Sample size was defined according to previous studies (Özen et al, ; Roth et al, ). For two‐group comparisons, Student t ‐test or multiple t tests were performed, as indicated in figure legends.…”

“…They show multiple responses to acute ischemic stroke (Cai et al, ; Kamouchi, Ago, Kuroda, & Kitazono, ), but only few studies so far have examined the role of pericytes in the chronic phase of stroke. These studies suggest that pericytes play an active role in tissue remodeling after stroke (Fernandez‐Klett et al, ; Makihara et al, ; Roth et al, ). In particular, it has been suggested that PDGFRß + pericytes detach from the vessel wall and migrate into the injured parenchyma where they form a dense network.…”

“…We have previously shown that loss of regulator of G‐protein signaling 5 (RGS5) in brain pericytes leads to a shift in the fate choice between the vascular and parenchymal location of pericytes after ischemic stroke (Roth et al, ). In RGS5‐knockout (KO) mice, we found a ca 50% reduction in parenchymal PDGFRß + density and an increased number of perivascular pericytes during the chronic phase after stroke.…”

“…In RGS5‐knockout (KO) mice, we found a ca 50% reduction in parenchymal PDGFRß + density and an increased number of perivascular pericytes during the chronic phase after stroke. The loss of RGS5 in pericytes and the associated preservation of perivascular pericytes improved the integrity of blood–brain barrier (BBB) and vessel remodeling (Roth et al, ). However, whether the spatial redistribution of PDGFRß + cells in these RGS5‐KO mice has an impact on the fibrotic and glial scar formation after stroke remains unknown.…”