Chronic valproate treatment enhances postischemic angiogenesis and promotes functional recovery in a rat model of ischemic stroke.
OBJECTIVE
Enhanced angiogenesis facilitates neurovascular remodeling processes and promotes brain functional recovery after stroke. Previous studies from our laboratory demonstrated that valproate (VPA), a histone deacetylase inhibitor, protects against experimental brain ischemia. The present study investigated whether VPA could enhance angiogenesis and promote long-term functional recovery after ischemic stroke.


METHODS
Male rats underwent middle cerebral artery occlusion for 60 minutes followed by reperfusion for up to 14 days. Assessed parameters were: locomotor function through the Rotarod test; infarct volume through T2-weighted MRI; microvessel density through immunohistochemistry; relative cerebral blood flow through perfusion-weighted imaging; protein levels of proangiogenic factors through Western blotting; and matrix metalloproteinase-2/9 activities through gelatin zymography.


RESULTS
Postischemic VPA treatment robustly improved the Rotarod performance of middle cerebral artery occlusion rats on Days 7 and 14 after ischemia and significantly reduced brain infarction on Day 14. Concurrently, VPA markedly enhanced microvessel density, facilitated endothelial cell proliferation, and increased relative cerebral blood flow in the ipsilateral cortex. The transcription factor hypoxia-inducible factor-1α and its downstream proangiogenic factors, vascular endothelial growth factor and matrix metalloproteinase-2/9, were upregulated after middle cerebral artery occlusion and significantly potentiated by VPA in the ipsilateral cortex. Acetylation of histone-H3 and H4 was robustly increased by chronic VPA treatment. The beneficial effects of VPA on Rotarod performance and microvessel density were abolished by hypoxia-inducible factor-1α inhibition.


CONCLUSIONS
Chronic VPA treatment enhances angiogenesis and promotes functional recovery after brain ischemia. These effects may involve histone deacetylase inhibition and upregulation of hypoxia-inducible factor-1α and its downstream proangiogenic factors vascular endothelial growth factor and matrix metalloproteinase-2/9.
Molecular Neurobiology Section, NIMH, NIH, 10 Center Drive, MSC 1363, Bethesda, MD 20892-1363, USA.
Zhifei
Z
Wang
Li-Kai
LK
Tsai
Jeeva
J
Munasinghe
Yan
Y
Leng
Emily Bame
EB
Fessler
Fairouz
F
Chibane
Peter
P
Leeds
De-Maw
DM
Chuang
D000818:Animals; D000927:Anticonvulsants / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015153:Blotting, Western; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D002544:Cerebral Infarction / Q000188:drug therapy / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology; D008124:Locomotion; D008279:Magnetic Resonance Imaging; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D004856:Postural Balance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology; D014635:Valproic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D000927:Anticonvulsants; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014635:Valproic Acid; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9