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 #
5R01NS065089-03
Application #
8286413
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
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$372,841
Indirect Cost
$158,466
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Itoh, Kanako; Maki, Takakuni; Shindo, Akihiro et al. (2016) Magnesium sulfate protects oligodendrocyte lineage cells in a rat cell-culture model of hypoxic-ischemic injury. Neurosci Res 106:66-9
Shindo, Akihiro; Maki, Takakuni; Mandeville, Emiri T et al. (2016) Astrocyte-Derived Pentraxin 3 Supports Blood-Brain Barrier Integrity Under Acute Phase of Stroke. Stroke 47:1094-100
Liang, Anna C; Mandeville, Emiri T; Maki, Takakuni et al. (2016) Effects of Aging on Neural Stem/Progenitor Cells and Oligodendrocyte Precursor Cells After Focal Cerebral Ischemia in Spontaneously Hypertensive Rats. Cell Transplant 25:705-14
Egawa, Naohiro; Lok, Josephine; Washida, Kazuo et al. (2016) Mechanisms of Axonal Damage and Repair after Central Nervous System Injury. Transl Stroke Res :
Arai, Ken (2016) Stroke Literature Synopses: Basic Science. Stroke 47:e250-e251
Arai, Ken (2016) Stroke Literature Synopses: Basic Science. Stroke 47:e40-1
Arai, Ken (2016) Stroke Literature Synopses: Basic Science. Stroke 47:e187
Maki, Takakuni; Maeda, Mitsuyo; Uemura, Maiko et al. (2015) Potential interactions between pericytes and oligodendrocyte precursor cells in perivascular regions of cerebral white matter. Neurosci Lett 597:164-9
Itoh, Kanako; Maki, Takakuni; Lok, Josephine et al. (2015) Mechanisms of cell-cell interaction in oligodendrogenesis and remyelination after stroke. Brain Res 1623:135-49
Arai, Ken (2015) Stroke Literature Synopses: Basic Science. Stroke 46:e250

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