Female Mice Are Resistant to Inward Remodeling of Parenchymal Arterioles Observed in Male Mice During Angiotensin II-Induced Hypertension

Hypertension increases risk of vascular cognitive impairment and dementia (VCID) by impairing the structure and function of cerebral arteries. These arterial changes result in chronic hypoperfusion of the brain parenchyma and, eventually, cognitive impairment. Epidemiological studies suggest a sex difference in development of VCID, with women being protected from its development until late in age. We have previously shown that angiotensin II (AngII)‐hypertension led to inward hypotrophic remodeling and decreased wall stress in the parenchymal arterioles (PAs) of male mice. This PA remodeling in AngII‐hypertension was associated with reduced cerebral perfusion, increased myogenic tone, and cognitive dysfunction. Female mice, however, were protected from memory impairments despite a similar increase in blood pressure and decrease in cerebral perfusion measured by scanning laser Doppler. We hypothesized that AngII‐hypertension in female mice will cause a decrease in cerebral perfusion measured by laser speckle contrast, as well as a decrease in outer diameter, lumen diameter, and wall thickness in the PAs. Sixteen to eighteen‐week‐old female C56BL/6 mice were treated with AngII (1200 ng/kg/min via osmotic mini‐pump) for four weeks. This dose was selected to produce a similar increase in blood pressure to the previously studied male mice. Sham mice served as control. Blood pressure was measured by tail‐cuff plethysmography and pial blood flow was measured. After euthanasia, brains were collected and PAs were isolated and mounted on a pressure myograph for assessment of spontaneous myogenic tone generation and structure. PA structure was assessed by increasing intralumenal pressure from 3mmHg to 120mmHg in 20mmHg increments. Results are presented as means ± SEM and PA data are reported at an intralumenal pressure of 40mmHg (n=5–12). Systolic blood pressure was increased (Sham: 141 ± 7, AngII: 179 ± 7mmHg; p<0.05) and cerebral perfusion was reduced in AngII‐hypertension (Sham: 328 ± 6, AngII: 288 ± 11 perfusion units; p<0.05). AngII infusion slightly decreased lumen (Sham: 49 ± 3, AngII: 42 ± 4μm; p=0.17) and outer (Sham: 57 ± 4, AngII: 48 ± 4μm; p=0.11) diameters, although not significantly. AngII‐hypertension reduced wall thickness (Sham: 4 ± 0.3, AngII: 3 ± 0.2μm; p<0.05) and wall area (Sham: 691 ± 83, AngII: 441 ± 52μm 2 ; p<0.05). PAs from female mice did not show reductions in wall stress (Sham: 241.8 ± 19, AngII: 268 ± 20dynes/cm 2 ; p>0.05) or generate more myogenic tone in response to hypertension (Sham: 27 ± 4, AngII: 22 ± 2%; p>0.05). While AngII‐hypertension resulted in reductions in lumen diameter, outer diameter, wall thickness, and wall stress in the PAs of male mice, PAs of female mice had only reduced wall thickness with modest reductions in lumen and outer diameters. Preliminary data suggest that females may be resistant to inward PA remodeling during AngII‐hypertension, despite similar reductions in cerebral blood flow as male mice. This potential protection of the cerebrovascular structure and myogenic tone generation could explain the absence of cognitive dysfunction in response to hypertension in female mice. Support or Funding Information 5T32GM092715‐14