Mineralocorticoid receptor antagonism prevents associated parenchymal arteriole remodeling

Abstract

Obesity, a major risk factor for cerebrovascular injury, is associated with an increase in mineralocorticoid receptor (MR) activation. Obesity induced middle cerebral artery remodeling can be prevented by MR antagonism. However, the role of obesity‐induced MR activation in cerebral parenchymal arteriole (PA) remodeling has not been defined. PAs are responsible for regulating microcirculatory blood flow and play a significant role in cerebrovascular resistance. We tested the hypothesis that obesity induced PA remodeling is remediated by MR antagonism. Three‐week‐old Sprague Dawley rats were randomized to a control or high fat (HF) diet. At 12 weeks of age, 50% of rats in each group began treatment with the MR antagonist, Canrenoic acid (20mg/kg/day; CAN). PA structure in 24 week‐old rats was assessed by pressure myography under calcium‐free and zero flow conditions at 60 mmHg. Data are presented as means ± SEM, n = 3–10 per group. MR antagonism increased systolic blood pressure in HF‐diet only (HF+Vehicle: 125 ± 6 vs HF+CAN: 153 ± 6 mmHg, p<0.01). At the time of euthanasia, HF‐fed rats, both vehicle and CAN treated, had more abdominal fat per body weight than controls (Control+Vehicle: 1.44 ± 0.37 vs HF+Vehicle: 4.31 ± 0.44 % of body weight, p<0.01; Control+CAN: 2.26 ± 0.33 vs HF+CAN: 4.70 ± 0.44 % of body weight, p<0.01). HF‐diet decreased PA outer diameter (Control+Vehicle: 85.00 ± 5.51 vs HF+Vehicle: 49.09 ± 3.55 μm, p<0.01) that was reversed by MR antagonism (HF+Vehicle: 49.09 ± 3.55 vs HF+CAN: 96.00 ± 3.49 μm, p<0.01). HF‐diet decreased PA lumen diameter (Control+Vehicle: 68.67 ± 6.74 vs HF+Vehicle: 34.59 ± 2.72 μm, p=0.028) that was reversed by MR antagonism (HF+Vehicle: 34.59 ± 2.72 vs HF+CAN: 73.17 ± 7.38 μm, p<0.01). HF‐diet tended to decrease PA vessel wall area (Control+Vehicle: 1948 ± 55 vs HF+Vehicle: 973 ± 148 μm2, p=0.103); MR antagonism increased wall area in HF‐fed rats (HF+Vehicle: 973 ± 148 vs HF+CAN: 2027 ± 234 μm2, p=0.016). Vascular remodeling is associated with cerebrovascular injury and cognitive impairment. Our results suggest that inward hypotrophic PA remodeling is MR dependent providing a potential therapeutic target to combat obesity‐induced cerebrovascular disease.Support or Funding InformationThis work was supported by National Institutes of Health (NIH) Grants R01‐HL‐137694‐01 to W. F. Jackson and A. M. Dorrance.