Abstract
We identified that the angiotensin receptor antagonist, candesartan, has profound neurovascular protective properties when administered after ischemic stroke and was associated with a proangiogenic state at least partly explained by vascular endothelial growth factor A (VEGFA). However, the spatial distribution of vascular endothelial growth factor (VEGF) isoforms and their receptors remained unknown. Protein analysis identified a significant increase in vascular endothelial grow factor B (VEGFB) in the cerebrospinal fluid (CSF) and the ischemic hemispheres (with increased VEGF receptor 1 activation) of treated animals (p<0.05) which was co-occurring with an increase in protein kinase B (Akt) phosphorylation (p<0.05). An increase in VEGFA protein in the contralesional hemisphere corresponded to a significant increase in vascular density at seven days (p<0.01) after stroke onset. Vascular restoration by candesartan after stroke maybe related to differential regional upregulation of VEGFB and VEGFA, promoting a "prosurvival state" in the ischemic hemisphere and angiogenesis in the contralesional side, respectively. These vascular changes in both hemispheres after effective treatment are likely to contribute to enhanced recovery after stroke.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Angiotensin Receptor Antagonists / pharmacology*
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Angiotensin Receptor Antagonists / therapeutic use
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Animals
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Blood Vessels / drug effects*
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Blood Vessels / metabolism
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Blood Vessels / pathology
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Blood Vessels / physiopathology
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Cerebrum / blood supply
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Cerebrum / drug effects*
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Cerebrum / metabolism
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Cerebrum / pathology
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Disease Models, Animal
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Gene Expression Regulation / drug effects*
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Hemorrhage / complications
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Hemorrhage / drug therapy
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MAP Kinase Signaling System / drug effects
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Male
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Polymerase Chain Reaction
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Protein Isoforms / cerebrospinal fluid
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Protein Isoforms / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Rats
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Rats, Wistar
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Receptors, Angiotensin / metabolism*
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Receptors, Vascular Endothelial Growth Factor / metabolism
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Stroke / complications
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Stroke / metabolism*
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Stroke / pathology
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Stroke / physiopathology
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Vascular Endothelial Growth Factor A / cerebrospinal fluid
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Vascular Endothelial Growth Factor A / metabolism*
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Angiotensin Receptor Antagonists
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Protein Isoforms
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Receptors, Angiotensin
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Vascular Endothelial Growth Factor A
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Receptors, Vascular Endothelial Growth Factor
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Proto-Oncogene Proteins c-akt
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p38 Mitogen-Activated Protein Kinases