Oligo-Vascular Signaling in Stroke White matter injury is a central event in the pathophysiology of diverse CNS disorders, including stroke and vascular dementia. But studies that investigate white matter are relatively uncommon in cerebrovascular research. Accumulating evidence suggest that cerebral endothelial cells have multiple functions in addition to conducting blood flow. Here, we hypothesize that cerebral endothelial cells secrete trophic factors to maintain oligodendrocyte (OL) and oligodendrocyte precursor cell (OPC) survival and function. Our 3 aims are:
Aim 1 : Dissect the cellular mechanisms of oligo-protection by endothelial-derived growth factors. Cultured rat OL/OPC will be subjected to oxygen-glucose deprivation. Endothelial conditioned media (Endo-CM) will be used to test whether growth factors from endothelial cells can protect OL/OPC cultures. We will investigate how Endo-CM promotes survival signaling (e.g. Akt) and decreases apoptosis in OL/OPC.
Aim 2 : Show that oxidative stress decreases endothelial growth factor production. We hypothesize that even without overt cell death, oxidatively-stressed endothelial cells will have reduced growth factor production. Cerebral endothelial cells will be exposed to oxidative stress, and we compare conditioned media from healthy endothelial cells vs oxidatively-stressed endothelial cells. Conditioned media from oxidatively-stressed endothelial cells should have less growth factors and thus, be less protective for OL/OPC against insults.
Aim 3 : Demonstrate that endothelial growth factors are important for OL/OPC in vivo. In various mouse models of cerebral ischemia, we will assess OL/OPC integrity in corpus callosum and striatum (i.e. white matter damage). Endothelial-specific gene delivery methods (liposome, scAAV9) will be used to modulate endothelial trophic factors in vivo. We predict that selectively increasing endothelial trophic factors protect white matter, whereas decreasing endothelial trophic factors makes white matter more vulnerable. Our pilot data (Arai and Lo, J Neurosci 2009) suggest that Endo-CM supports OPC proliferation via specific signaling pathways and oxidative stress interferes with oligovascular coupling. In this proposal, we will build on these initial findings to show that Endo-CM can truly prevent cell death in OL/OPC. And most importantly, we aim to show that oligovascular coupling protects against stroke in vivo. These experiments should provide evidence to show that trophic coupling between endothelium and OL/OPC maintains and protects white matter.

Public Health Relevance

Although white matter damage is a central event in the pathophysiology of diverse CNS disorders such as stroke and vascular dementia, studies that investigate white matter are relatively uncommon in basic cerebrovascular research. Here we propose that cerebral endothelial cells secrete trophic factors to maintain oligodendrocyte survival and function. Our studies will provide evidence of the novel idea that trophic coupling between endothelium and oligodendrocyte plays a key role in protecting white matter in stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS065089-05
Application #
8685341
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Koenig, James I
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Arai, Ken (2018) Stroke Literature Synopses: Basic Science (2018/May). Stroke 49:e270
Takase, Hajime; Liang, Anna C; Miyamoto, Nobukazu et al. (2018) Protective effects of a radical scavenger edaravone on oligodendrocyte precursor cells against oxidative stress. Neurosci Lett 668:120-125
Arai, Ken (2018) Stroke Literature Synopses: Basic Science. Stroke :
Maki, Takakuni; Choi, Yoon Kyung; Miyamoto, Nobukazu et al. (2018) A-Kinase Anchor Protein 12 Is Required for Oligodendrocyte Differentiation in Adult White Matter. Stem Cells 36:751-760
Arai, Ken (2018) Stroke Literature Synopses: Basic Science (2017/Dec). Stroke 49:e39-e40
Maki, Takakuni; Morancho, Anna; Martinez-San Segundo, Pablo et al. (2018) Endothelial Progenitor Cell Secretome and Oligovascular Repair in a Mouse Model of Prolonged Cerebral Hypoperfusion. Stroke 49:1003-1010
Arai, Ken (2017) Stroke Literature Synopses: Basic Science (2017/May). Stroke 48:e193-e194
Arai, Ken (2017) Stroke Literature Synopses: Basic Science. Stroke 48:e193-e194
Arai, Ken (2017) Stroke Literature Synopses: Basic Science. Stroke 48:e85-e86
Arai, Ken (2017) Stroke Literature Synopses: Basic Science (2017/Aug). Stroke 48:e336-e337

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