Sexual Dimorphisms in Hypertension‐Associated Cerebrovascular Damage

Abstract

Hypertension is a major risk factor for cerebral small vessel disease (CVSD), which increases stroke and dementia risk. Hypertension alters artery structure, impairing blood flow regulation and preventing nutrient delivery to the brain parenchyma. We previously showed angiotensin II (AngII)-hypertension in male mice reduces overall pial blood flow measured by scanning laser Doppler and causes inward hypotrophic remodeling in cerebral parenchymal arterioles (PAs). Epidemiological evidence suggests sex differences exist in CVSD, with large vessel damage occurring more in males and small vessel damage occurring more in females. We hypothesized hypertensive male and female mice would have reductions in pial blood flow measured by laser speckle contrast and inward hypotrophic remodeling in PAs. AngII-filled osmotic minipumps (800ng/kg/min, 4 weeks) were implanted in 16-18-week-old male C56BL/6 mice. Age-matched female mice received either an AngII dose that matches the dose used in male mice (800ng/kg/min) or a higher dose (1200ng/kg/day) that produces an elevation in blood pressure similar to male mice. Sham mice served as control. Blood pressure was measured by tail-cuff plethysmography. Pial artery blood flow was measured in the frontal, parietal, and temporal areas of both brain hemispheres. After euthanasia, PAs were isolated and mounted on a pressure myograph for structure assessment by increasing intraluminal pressure from 3 to 120mmHg in 20mmHg increments. Data are presented as means ± SEM (n=6-9). PA data are reported at an intraluminal pressure of 40mmHg. Systolic blood pressure was elevated in AngII-treated male mice (sham: 133 ± 10, AngII: 181 ± 11mmHg; p<0.05) and in 1200ng AngII-treated female mice (sham: 146 ± 8, 800ng AngII: 161 ± 13, 1200ng AngII: 179* ± 7mmHg; p<0.05) vs sham. There was a sex difference in blood flow alterations during hypertension. Male AngII treated mice had reduced flow in the parietal region (sham: 361 ± 19, AngII: 301 ± 9.3A.U.; p<0.05) but not frontal (sham: 359 ± 19, AngII: 327 ± 11A.U.; p=0.19) or temporal regions (sham: 292 ± 13, AngII: 284 ± 15A.U.; p=0.68) vs sham. AngII treated female mice had reductions in pial flow in the parietal (sham: 403 ± 9, 800ng AngII: 336* ± 19, 1200ng AngII: 314* ± 33 A.U.; p<0.05), frontal (sham: 378 ± 7, 800ng AngII: 314* ± 13, 1200ng AngII: 279* ± 24 A.U.; p<0.05), and temporal (sham: 338 ± 8.4, 800ng AngII: 273* ± 11, 1200ng AngII: 278* ± 25 A.U.; p<0.05) regions vs sham. PAs from male AngII mice had reduced outer diameter (sham: 56 ± 3, AngII: 46 ± 2μm; p<0.05), lumen diameter (sham: 47 ± 1, AngII: 40 ± 2μm; p=0.05), and wall area (sham: 719 ± 115, AngII: 405 ± 24μm2; p<0.05) vs sham, reproducing previous findings. PAs from AngII treated female mice did not exhibit significant reductions in outer diameter (sham: 57 ± 3, 800ng AngII: 50 ± 5, 1200ng AngII: 47 ± 4μm; p=0.17) or lumen diameter (sham: 49 ± 2, 800ng AngII: 43 ± 5, 1200ng AngII: 41 ± 4μm; p=0.22, but showed a modest reduction in wall area (sham: 647 ± 64, 800ng AngII: 534 ± 78, 1200ng AngII: 439 ± 58μm2; p=0.09) vs sham. These data suggest the mechanism of hypertension-induced vascular damage differs between males and females. Understanding sex differences in CVSD is critical for dementia and stroke prevention.