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Experimental chronic cerebral hypoperfusion results in decreased pericyte coverage and increased blood-brain barrier
Qinghai Liu1, Ryan Radwanski1, Robin Babadjouni1
11 Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Abstract:
Murine chronic cerebral hypoperfusion (CCH) results in white matter (WM) injury and behavioral deficits. Pericytes influence blood-brain barrier (BBB) integrity and cerebral blood flow. Under hypoxic conditions, pericytes detach from perivascular locations increasing vessel permeability and neuronal injury. This study characterizes the time course of BBB dysfunction and pericyte coverage following murine experimental CCH secondary to bilateral carotid artery stenosis (BCAS). Mice underwent BCAS or sham operation. On post-procedure days 1, 3, 7 and 30, corpus callosum BBB permeability was characterized using Evans blue (EB) extravasation and IgG staining and pericyte coverage/count was calculated. The BCAS cohort demonstrated increased EB extravasation on postoperative days 1 ( p = 0.003) 3 ( p = 0.002), and 7 ( p = 0.001) when compared to sham mice. Further, EB extravasation was significantly greater ( p = 0.05) at day 3 than at day 30 in BCAS mice. BCAS mice demonstrated a nadir in pericyte coverage and count on post-operative day 3 ( p < 0.05, compared to day 7, day 30 and sham). Decreased pericyte coverage/count and increased BBB permeability are most pronounced on postoperative day 3 following murine CCH. This precedes any notable WM injury or behavioral deficits.
Insights
Chronic cerebral hypoperfusion in mice causes blood-brain barrier (BBB) dysfunction and pericyte loss. These changes are most severe on day 3, preceding white matter injury.
Area of Science:
- Neuroscience
- Cerebrovascular Biology
- White Matter Injury
Background:
- Chronic cerebral hypoperfusion (CCH) in mice leads to white matter (WM) damage and behavioral impairments.
- Pericytes are crucial for maintaining blood-brain barrier (BBB) integrity and regulating cerebral blood flow.
- Hypoxia causes pericyte detachment, increasing vessel permeability and neuronal damage.
Purpose of the Study:
- To investigate the temporal dynamics of BBB dysfunction and pericyte coverage following experimental CCH in mice.
- To correlate BBB changes with pericyte alterations in a murine model of CCH induced by bilateral carotid artery stenosis (BCAS).
Main Methods:
- Mice underwent either BCAS or a sham operation.
- Blood-brain barrier permeability was assessed using Evans blue (EB) extravasation and IgG staining on days 1, 3, 7, and 30 post-procedure.
- Pericyte coverage and count were quantified in the corpus callosum.
Main Results:
- BCAS mice exhibited significantly increased EB extravasation on days 1, 3, and 7 compared to sham controls (p < 0.003).
- EB extravasation was higher on day 3 than day 30 in BCAS mice (p = 0.05).
- Pericyte coverage and count reached their lowest point on day 3 post-operation in BCAS mice (p < 0.05 vs. day 7, day 30, and sham).
Conclusions:
- Reduced pericyte coverage and increased BBB permeability are most prominent on postoperative day 3 in murine CCH.
- These BBB and pericyte changes occur before the onset of observable WM injury or behavioral deficits.
