Candesartan augments ischemia-induced proangiogenic state and results in sustained improvement after stroke.
OBJECTIVE
We have shown that acute treatment with candesartan in an experimental model of stroke resulted in vascular protection and improved outcomes at 24 hours poststroke, but the mechanisms are unknown. We now examine effects of candesartan on proangiogenic factors and 7-day outcomes using the same treatment paradigm.


METHODS
Male Wistar rats underwent 3 hours of middle cerebral artery occlusion followed by reperfusion. A single dose of 1 mg/kg candesartan intravenously was given at reperfusion. Animals received neurobehavioral testing before middle cerebral artery occlusion, at 24 hours after middle cerebral artery occlusion, and at 7 days. Blood pressure was measured by telemetry. Animals euthanized at 24 hours had brain tissue and cerebrospinal fluid collected for matrix metalloproteinase activity, vascular endothelial growth factor expression, and tube formation assay. Neurobehavioral testing included elevated body swing test, Bederson, beam walk, and paw grasp. Cerebrovascular density was quantified using immunohistochemistry at 24 hours and 7 days.


RESULTS
Matrix metalloproteinase-2 activity and vascular endothelial growth factor expression were higher (P=0.035, P=0.042, respectively) and cerebrospinal fluid was significantly more proangiogenic (5x tube formation; P=0.002) in the candesartan group at 24 hours. Although no difference was seen in infarct size at 7 days, treatment improved Bederson scores (2.1 versus 2.9, P=0.0083), elevated body swing test (22.9 versus 39.4, P=0.021), and paw grasp (1.29 versus 2.88, P=0.0001) at 7 days. Candesartan treatment resulted in increased vascular density in the striatum at 7 days (P=0.037).


CONCLUSIONS
Candesartan after reperfusion augments ischemia-induced angiogenic state and provides long-term benefits. The beneficial effects may involve vascular protection and enhancement of early angiogenic remodeling.
Kozak
Anna
A
University of Georgia College of Pharmacy, Veterans Administration Medical Center, Augusta, GA 30912-2450, USA.
Ergul
Adviye
A
El-Remessy
Azza B
AB
Johnson
Maribeth H
MH
Machado
Livia S
LS
Elewa
Hazem F
HF
Abdelsaid
Mohammed
M
Wiley
Daniel C
DC
Fagan
Susan C
SC
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000523:psychology; D002199:Capillary Permeability / Q000187:drug effects; D042783:Endothelial Cells / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D007797:Laminin / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D008870:Microtubules / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology / Q000523:psychology; D013777:Tetrazoles / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007797:Laminin; D013777:Tetrazoles; D042461:Vascular Endothelial Growth Factor A; D020782:Matrix Metalloproteinases; C081643:candesartan