Stimulation of Angiotensin II Receptor 2 Preserves Cognitive Function Post Stroke and is Associated with an Enhanced Cerebral Vascular Density in Female Rats.
Authors: Eldahshan Wael , Sayed Mohammed A. , Awad Mohamed E. , Ahmed Heba , Gillis Ellen , Althomali Waleed , Pillai Bindu , Alshammari Abdulkarim , Jackson Ladonya , Sullivan Jennifer , Elsalanty Mohammed , Ergul Adviye , Fagan Susan C. 
Published: April 2020

Angiotensin signaling is known to be sexually dimorphic and although a well‐studied target for intervention in stroke and cognitive impairment in males, studies in females 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 stimulation of the angiotensin receptor subtype 2 (AT2R) with 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 hour of middle cerebral artery occlusion (MCAO) using the suture model. At 24 hours, 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. In a separate cohort of female SHRs, mean arterial pressure (MAP) was monitored continuously using telemetry units (Data Sciences International, St. Paul, MN). Rats were then randomized to the following treatment groups: low dose C21 (0.216 mg/kg/day, SC, Alzet Pump, Cupertino, CA), high dose C21 (0.432 mg/kg/day, SC), or surgical sham control. MAP was monitored for an additional 2 weeks. Outcomes measured were sensorimotor and cognitive function, brain structure by MRI and vascular architecture by microCT Angiography. Compound 21 preserved cognitive function, specifically spatial memory, without a significant effect on sensorimotor function or infarct size as measured by MRI. Interestingly, animals treated with C21 had a 2‐fold increase in vascular density in the ischemic hemisphere at 6 weeks, reflecting both arteriogenesis and angiogenesis. Neither low nor high dose C21 affected MAP. In conclusion, C21 prevented cognitive impairment after stroke independent of changes in MAP, likely through a mechanism involving vascular protection and restoration.

Support or Funding Information

R01NS104573 to AE and SCF. Jowdy Professorship to SCF

Data are mean ± SEM

Saline

C21

MAP (mmHg)

128±2

Low dose: 136±54#
High Dose: 134±4#

Bederson at Randomization

2.9 ± 0.4

2.5 ± 0.42#

Bederson at 6 weeks

5 ± 0.33 N=10

5.87 ± 0.47 N =8#

Infarct Size by MRI (% contralateral side)

18.74 ±1.82 N=6

14.76 ± 4.16 N=5#

Sham

Stroked

Saline

C21

Saline

C21

Passive Avoidance (Latency in seconds)

276 ± 8.9, N=5

286.3 ± 3.8, N=4

91.83 ± 50.14, N=6

279 ± 5.8a, N=5

Object Placement Test (% time with moved object)

55.06 ± 4.0
N=9

45.27 ± 4.0
N=8

41.77 ± 3.72
N=10

71.6 ± 6.9a
N8

MicroCT Angiography

Vessel Volume/Total Volume

0.45 ± 0.08
N=4

0.51 ± 0.07
N=4

0.29 ± 0.06
N=4

0.81 ± 0.09a
N=3

Vessel Number

0.04±0.007

0.04 ± 0.006

0.03 ± 0.007

0.08 ± 0.011a

Vessel Thickness

0.1002± 0.007

0.1101± 0.007

0.0902± 0.007

0.0948± 0.011#

Vessel Separation

1.59± 0.03

1.48 ± 0.16

1.91± 0.14

1.37± 0.12b

#p>0.05 vs saline,

apost‐hoc Bonferoni p< 0.01 vs stroke saline,

bpost‐hoc Bonferoni p<0.05 vs stroke saline.