Abstract
Blood-brain barrier (BBB) damage is a critical event in ischemic stroke, contributing to aggravated brain damage. Endothelial cell form a major component of the BBB, but its regulation in stroke has yet to be clarified. We investigated the function of Yes-associated protein 1 (YAP) in the endothelium on BBB breakdown during cerebral ischemia/reperfusion (I/R) injury. The effects of YAP on BBB dysfunction were explored in middle cerebral artery occlusion/reperfusion (MCAO/R)-injury model mice and using brain microvascular endothelial cells (BMEC) exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) injury. The degree of brain injury was estimated using staining (2,3,5-Triphenyltetrazolium chloride, hematoxylin and eosin) and the detection of cerebral blood flow. BBB breakdown was investigated by examining the leakage of Evans Blue dye and evaluating the expression of tight junction (TJ)-associated proteins and matrix metallopeptidase (MMP) 2 and 9. YAP expression was up-regulated in the nucleus of BMEC after cerebral I/R injury. Verteporfin (YAP inhibitor) down-regulated YAP expression in the nucleus and improved BBB hyperpermeability and TJ integrity disruption stimulated by cerebral I/R. YAP-targeted small interfering RNA (siRNA) exerted the same effects in BMEC cells exposed to OGD/R injury. Our findings provide new insights into the contributions made by YAP to the maintenance of BBB integrity and highlight the potential for YAP to serve as a therapeutic target to modulate BBB integrity following ischemic stroke and related cerebrovascular diseases.
Highlights
Ischemic stroke is often accompanied by vascular dysfunction due to damage to the blood-brain barrier (BBB) (Feigin et al, 2018; Ozen et al, 2018)
To determine the specific role played by Yesassociated protein 1 (YAP) in ischemic stroke, YAP expression levels were evaluated in the brain after middle cerebral artery occlusion/reperfusion (MCAO/R) injury using western blotting and IF analyses
After 1 h of cerebral ischemia and 24 h of reperfusion, the expression levels of YAP and p-YAP were reduced in the cytoplasm, and the expression level of YAP was significantly increased in the nucleus (Figure 1 and Supplementary Figures S3–5)
Summary
Ischemic stroke is often accompanied by vascular dysfunction due to damage to the blood-brain barrier (BBB) (Feigin et al, 2018; Ozen et al, 2018). The BBB is a specialized barrier comprised of endothelial cells (ECs), tight junctions (TJs), pericytes, astrocytic end-feet processes, and the basement membrane. These components are crucial for the establishment of a highly regulated microenvironment, which ensures appropriate neuronal function (Moskowitz et al, 2010; Lallukka et al, 2018; Sweeney et al, 2019). The appropriate regulation and maintenance of the barrier integrity of the ECs that line within blood vessels represent an essential feature of the BBB. The prevention of early cytoskeletal changes in microvascular ECs can attenuate BBB breakdown and secondary tissue injury, resulting in the amelioration of long-term neurological deficits (Fernandez-Klett et al, 2013; Hall et al, 2014). The molecular mechanisms that underlie the regulation of EC function and the associated BBB alterations that occur under pathological conditions remain incompletely understood
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