TY - JOUR
T1 - Stimulation of angiotensin II receptor 2 preserves cognitive function and is associated with an enhanced cerebral vascular density after stroke
AU - Eldahshan, Wael
AU - Sayed, Mohammed A.
AU - Awad, Mohamed E.
AU - Ahmed, Heba A.
AU - Gillis, Ellen
AU - Althomali, Waleed
AU - Pillai, Bindu
AU - Alshammari, Abdulkarim
AU - Jackson, Ladonya
AU - Dong, Guangkuo
AU - Sullivan, Jennifer C.
AU - Cooley, Marion A.
AU - Elsalanty, Mohammed
AU - Ergul, Adviye
AU - Fagan, Susan C.
N1 - Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/12
Y1 - 2021/12
N2 - Angiotensin signaling is known to be sexually dimorphic. Although it is a well-studied target for intervention in stroke and cognitive impairment, female studies are rare. With females suffering a disproportionately greater negative impact of stroke and dementia vs. males, effective interventions are of utmost urgency. The aim of the current study was to determine the impact of activation of the angiotensin II type 2 receptor (AT2R) with the agonist compound 21 (C21) on the development of post-stroke cognitive impairment, after experimental ischemic stroke. Ovariectomized (OVX) spontaneously hypertensive rats (SHRs) were subjected to 1 h of middle cerebral artery occlusion (MCAO). At 24 h, rats with a significant neurologic deficit were randomized to receive either saline or C21 (0.03 mg/kg/day) intraperitoneally (IP) for 5 days, then orally (0.12 mg/kg/day) for a total of 6 weeks. Cognitive function, brain structure by MRI and vascular architecture by microCT angiography were measured. C21 preserved cognitive function, specifically spatial memory, and improved vascular density in the ischemic hemisphere at 6 weeks, reflecting both arteriogenesis and angiogenesis. In conclusion, C21 prevented cognitive impairment after stroke, likely through a mechanism involving vascular protection and restoration.
AB - Angiotensin signaling is known to be sexually dimorphic. Although it is a well-studied target for intervention in stroke and cognitive impairment, female studies are rare. With females suffering a disproportionately greater negative impact of stroke and dementia vs. males, effective interventions are of utmost urgency. The aim of the current study was to determine the impact of activation of the angiotensin II type 2 receptor (AT2R) with the agonist compound 21 (C21) on the development of post-stroke cognitive impairment, after experimental ischemic stroke. Ovariectomized (OVX) spontaneously hypertensive rats (SHRs) were subjected to 1 h of middle cerebral artery occlusion (MCAO). At 24 h, rats with a significant neurologic deficit were randomized to receive either saline or C21 (0.03 mg/kg/day) intraperitoneally (IP) for 5 days, then orally (0.12 mg/kg/day) for a total of 6 weeks. Cognitive function, brain structure by MRI and vascular architecture by microCT angiography were measured. C21 preserved cognitive function, specifically spatial memory, and improved vascular density in the ischemic hemisphere at 6 weeks, reflecting both arteriogenesis and angiogenesis. In conclusion, C21 prevented cognitive impairment after stroke, likely through a mechanism involving vascular protection and restoration.
KW - Angiotensin II receptor subtype 2 (AT2R)
KW - Female rodents
KW - Post-stroke cognitive impairment (PSCI)
KW - Spontaneously hypertensive rats (SHRs)
KW - microCT angiography
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U2 - 10.1016/j.vph.2021.106904
DO - 10.1016/j.vph.2021.106904
M3 - Article
C2 - 34481068
AN - SCOPUS:85115010691
SN - 1537-1891
VL - 141
JO - Vascular Pharmacology
JF - Vascular Pharmacology
M1 - 106904
ER -