Redistribution of PDGFRβ cells and NG2DsRed pericytes at the cerebrovasculature after status epilepticus

Abstract

Purpose The role of cerebrovascular dysfunction in seizure disorders is recognized. Blood-brain barrier (BBB) damage in epilepsy has been linked to endothelial and glial pathophysiological changes. Little is known about the involvement of pericytes, a cell type that contributes to BBB function. Methods NG2DsRed mice were used to visualize cerebrovascular pericytes. The pattern of vascular and parenchymal distribution of platelet-derived growth factor receptor beta (PDGFRβ) cells was evaluated by immunohistochemistry. Status epilepticus was induced in NG2DsRed or C57BL/6J mice by intraperitoneal kainic acid (KA). Animals were perfused intracardially using FITC-Dextran or FITC-Albumin to visualize the cerebrovasculature. Colocalization was performed between NG2DsRed, PDGFRβ and microglia IBA-1. Confocal 3D vessel reconstruction was used to visualize changes in cell morphology and position. PDGFRβ expression was also evaluated in vitro using organotypic hippocampal cultures (OHC) treated with kainic acid to induce seizure-like activity. Co-localization of PDGFRβ with the vascular marker RECA-1 and NG2 was performed. Finally, we assessed the expression of PDGFRβ in brain specimens obtained from a cohort of patients affected by drug resistant epilepsy compared to available autoptic brain. Results In vivo, severe status epilepticus (SE) altered NG2DsRed vascular coverage. We found dishomogenous NG2DsRed perivascular ramifications after SE and compared to control. Concomitantly, PDGFRβ+ cells re-distributed towards the cerebrovasculature after severe SE. Cerebrovascular NG2DsRed partially colocalized with PDGFRβ+ while parenchymal PDGFRβ+ cells did not colocalize with IBA-1+ microglia. Using in vitro OHC we found decreased NG2 vascular staining and increased PDGFRβ+ ramifications associated with RECA-1+ microvessels after seizure-like activity. Cellular PDGFRβ and NG2+ colocalization was observed in the parenchyma. Finally, analysis of human TLE brains revealed perivascular and parenchymal PDGFRβ+ cells distribution resembling the murine in vivo and in vitro results. PDGFRβ+ cells at the cerebrovasculature were more frequent in TLE brain tissues as compared to the autoptic control. Conclusions The rearrangement of PDGFRβ+ and vascular NG2DsRed cells after SE suggest a possible involvement of pericytes in the cerebrovascular modifications observed in epilepsy. The functional role of vascular-parenchymal PDGFRβ+ cell redistribution and the relevance of a pericyte response to SE remain to be fully elucidated.

Seizure‐induced microvascular injury is associated with impaired neurovascular coupling and blood–brain barrier dysfunction

“…Among the components of the BBB neurovascular unit, pericytes may be of particular relevance, as they play a crucial role in BBB integrity and contribute to microcirculatory dysfunction . Moreover, pericytes were shown to redistribute following kainic acid–induced status epilepticus as well as in chronic epileptic tissue …”

Perivascular Mesenchymal Stem Cells From the Adult Human Brain Harbor No Instrinsic Neuroectodermal but High Mesodermal Differentiation Potential

“…Interestingly, a very recent report noted an increase of platelet-derived growth factor receptor beta-positive (PDGFRb+) cells in patients with temporal lobe epilepsy [18], suggesting that these cells might be activated for endogenous repair strategies.…”

High-resolution in vivo optical imaging of stroke injury and repair

“…Several advanced labeling strategies based on XFPs are available for tagging smooth muscle cells and pericytes (Armulik et al, 2011; Hall et al, 2014; Iliff et al, 2013; Milesi et al, 2014; Thrane et al, 2013). Understanding the role of pericytes in microvascular blood flow control is critically important for understanding regulation of resting CBF and functional hyperemia (Hall et al, 2014), as well as cerebral ischemia and reperfusion (Yemisci et al, 2009).…”

“…Understanding the role of pericytes in microvascular blood flow control is critically important for understanding regulation of resting CBF and functional hyperemia (Hall et al, 2014), as well as cerebral ischemia and reperfusion (Yemisci et al, 2009). In a study by Milesi et al (2014), mice expressing DsRed fluorescent protein under NG2 promoter (Zhu et al, 2008) were used to quantify the NG2-DsRed perivascular ramifications after status epilepticus (SE) (Fig. 3B).…”

“…Arrowheads indicate pericyte soma. Adapted with permission from Milesi et al (2014). (C) Integrity of cortical blood vessel tight junctions is impaired at late but not early time points after transient MCAO in live Tg eGFP-Claudin5 mice.…”