Pires Paulo W, McClain Jonathon L, Hayoz Sebastian F, Dorrance Anne M
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA.
Department of Pharmacology, Center for Cardiovascular Research, University of Nevada School of Medicine, Reno, NV, USA.
Microcirculation. 2018 Jul;25(5):e12460. doi: 10.1111/micc.12460. Epub 2018 Jun 7.
Midlife obesity is a risk factor for dementia development. Obesity has also been linked to hyperaldosteronism, and this can be modeled in rats by high fat (HF) feeding from weaning. Aldosterone, or activation of the mineralocorticoid receptor (MR) causes cerebrovascular injury in lean hypertensive rats. We hypothesized that rats fed a HF diet would show inward middle cerebral artery (MCA) remodeling that could be prevented by MR antagonism. We further proposed that the cerebral artery remodeling would be associated with white mater injury.
Three-week-old male Sprague-Dawley rats were fed a HF diet ± the MR antagonist canrenoic acid (Canr) for 17 weeks. Control rats received normal chow (control NC). MCA structure was assessed by pressure myography.
The MCAs from HF fed rats had smaller lumens and thicker walls when compared to arteries from control NC rats; Canr prevented the MCA remodeling associated with HF feeding. HF feeding increased the mRNA expression of markers of cell proliferation and vascular inflammation in cerebral arteries and Canr treatment prevented this. White mater injury was increased in the rats fed the HF diet and this was reduced by Canr treatment. The expression of doublecortin, a marker of new and immature neurons was reduced in HF fed rats, and MR antagonism normalized this.
These data suggest that HF feeding leads to MR dependent remodeling of the MCA and this is associated with markers of dementia development.
中年肥胖是痴呆症发生的一个风险因素。肥胖还与醛固酮增多症有关，从断奶开始用高脂肪（HF）饲料喂养大鼠可模拟这种情况。在瘦型高血压大鼠中，醛固酮或盐皮质激素受体（MR）的激活会导致脑血管损伤。我们假设，喂食HF饮食的大鼠会出现大脑中动脉（MCA）内向重塑，而MR拮抗作用可以预防这种重塑。我们进一步提出，脑动脉重塑将与白质损伤有关。
给3周龄雄性Sprague-Dawley大鼠喂食HF饮食±MR拮抗剂坎利酮酸（Canr），持续17周。对照大鼠喂食正常饲料（对照NC）。通过压力肌动描记法评估MCA结构。
与对照NC大鼠的动脉相比，喂食HF饮食的大鼠的MCA管腔更小，管壁更厚；Canr可预防与HF喂养相关的MCA重塑。HF喂养增加了脑动脉中细胞增殖和血管炎症标志物的mRNA表达，而Canr治疗可预防这种情况。喂食HF饮食的大鼠白质损伤增加，而Canr治疗可减轻这种损伤。在喂食HF饮食的大鼠中，新的和未成熟神经元的标志物双皮质素的表达降低，而MR拮抗作用使其恢复正常。
这些数据表明，HF喂养会导致MR依赖的MCA重塑，这与痴呆症发生的标志物有关。
