Endothelial cells (EC) are the major cellular component of the blood brain barrier (BBB). Endothelial damage or dysfunction, which occurs early after cerebral ischemic/reperfusion (I/R), contributes critically to the BBB disruption and development of neurovascular injury after stroke. Elucidation of the mechanisms by which EC integrity and function are compromised after I/R is an essential step in identifying novel EC-protecting strategies that may reduce the progressive brain damage and improve long-term neurological outcome after stroke. The pathological breach of BBB integrity is inevitably associated with structural alterations in EC, including reorganization of the actin cytoskeleton and redistribution of junctional proteins. Our recent studies revealed that the structural changes in EC after I/R not only are critical for the early (30 min-3 h) BBB leakage to smaller molecules, but sensitize microvessels to matrix metalloproteinase (MMP)-mediated secondary BBB disruption and leakage to larger molecules. An episode of I/R initiates oxidative stress-mediated inflammatory processes in EC, which facilitate the recruitment and infiltration of peripheral immune cells (including neutrophils and monocytes). The resulting accumulation of immune cells, pro-inflammatory mediators, and neutrophil-derived proteases further promote BBB disruption and the progression of brain infarct. Therefore, restoring EC structure while simultaneously blocking inflammation in microvasculature may provide a unified and innovative therapeutic strategy for brain protection against I/R injury. Peroxiredoxin 4 (Prx4) is a member in a family of antioxidant enzymes (Prx1-6). We recently discovered that Prx4 is expressed exclusively in EC in the brain, and its level is transiently elevated after I/R. However, the functional role of Prx4 in vascular integrity following I/R and its underlying mechanism of action have not been explored in CNS. This proposal will test the overarching hypothesis that endothelial Prx4 protects against I/R neurovascular injury through dual mechanisms: 1) Prx4 prevents the initial induction of BBB disruption by stabilizing cytoskeletal organization in EC via a distinctive signaling pathway; and 2) Prx4 inhibits EC-initiated inflammation in the microvasculature. Using transgenic mice overexpressing Prx4 selectively in ECs, we have obtained critical evidence to support this hypothesis.
Three specific Aims are proposed to test the following working hypotheses: 1) Endothelium-targeted overexpression of Prx4 is sufficient to confer protection against BBB damage and improve long-term outcome after I/R. 2) Prx4 inhibits the initial induction of BBB disruption and the inflammatory responses in ECs via modulating the ROCK/MCL/Actin signaling pathway and the ASK1/p38 signaling pathway, respectively. 3) Administration of cell membrane-permeable TAT-Prx4 protects BBB integrity and improves outcomes in stroke mice. In sum, the proposed studies investigate novel BBB- protecting effect and mechanism of Prx4 in cerebral I/R. A positive outcome of the study will help develop a novel and clinical relevant therapeutic strategy against stroke and its devastating neurovascular sequelae.
Stroke is a devastating clinical condition for which an effective neuroprotective treatment is currently unavailable. We have identified the newly characterized anti-oxidant protein, Peroxiredoxin (Prx4), as a promising therapeutic agent for the treatment of ischemic stroke. The objective of this proposal is to investigate whether overexpression of Prx4 in endothelial cells protects against endothelial dysfunction, blood brain barrier damage, and neurovascular injury and confers long-term neuroprotection after ischemic/reperfusion brain injury. This information will be valuable for future development of new therapeutic strategies for the treatment of stroke and, possibly, other neurological disorders.
|Hu, Xiaoming; De Silva, T Michael; Chen, Jun et al. (2017) Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke. Circ Res 120:449-471|
|Mao, Leilei; Li, Peiying; Zhu, Wen et al. (2017) Regulatory T cells ameliorate tissue plasminogen activator-induced brain haemorrhage after stroke. Brain 140:1914-1931|
|Jiang, Xiaoyan; Andjelkovic, Anuska V; Zhu, Ling et al. (2017) Blood-brain barrier dysfunction and recovery after ischemic stroke. Prog Neurobiol :|
|Cai, Wei; Liu, Huan; Zhao, Jingyan et al. (2017) Pericytes in Brain Injury and Repair After Ischemic Stroke. Transl Stroke Res 8:107-121|
|Cai, Wei; Zhang, Kai; Li, Peiying et al. (2017) Dysfunction of the neurovascular unit in ischemic stroke and neurodegenerative diseases: An aging effect. Ageing Res Rev 34:77-87|
|Shi, Yejie; Jiang, Xiaoyan; Zhang, Lili et al. (2017) Endothelium-targeted overexpression of heat shock protein 27 ameliorates blood-brain barrier disruption after ischemic brain injury. Proc Natl Acad Sci U S A 114:E1243-E1252|
|Liu, Xiangrong; Liu, Jia; Zhao, Shangfeng et al. (2016) Interleukin-4 Is Essential for Microglia/Macrophage M2 Polarization and Long-Term Recovery After Cerebral Ischemia. Stroke 47:498-504|
|Zhang, Wenting; Zhang, Hui; Mu, Hongfeng et al. (2016) Omega-3 polyunsaturated fatty acids mitigate blood-brain barrier disruption after hypoxic-ischemic brain injury. Neurobiol Dis 91:37-46|
|Shi, Yejie; Zhang, Lili; Pu, Hongjian et al. (2016) Rapid endothelial cytoskeletal reorganization enables early blood-brain barrier disruption and long-term ischaemic reperfusion brain injury. Nat Commun 7:10523|
|Shi, Yejie; Leak, Rehana K; Keep, Richard F et al. (2016) Translational Stroke Research on Blood-Brain Barrier Damage: Challenges, Perspectives, and Goals. Transl Stroke Res 7:89-92|
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