Matin Nusrat, Fisher Courtney, Jackson William F, Dorrance Anne M
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan.
Am J Physiol Heart Circ Physiol. 2016 May 15;310(10):H1321-9. doi: 10.1152/ajpheart.00890.2015. Epub 2016 Mar 11.
Chronic cerebral hypoperfusion is a risk factor for cognitive impairment. Reduced blood flow through the common carotid arteries induced by bilateral carotid artery stenosis (BCAS) is a physiologically relevant model of chronic cerebral hypoperfusion. We hypothesized that BCAS in 20-wk-old Wistar-Kyoto (WKY) rats would impair cognitive function and lead to reduced endothelium-dependent dilation and outward remodeling in the parenchymal arterioles (PAs). After 8 wk of BCAS, both short-term memory and spatial discrimination abilities were impaired. In vivo assessment of cerebrovascular reserve capacity showed a severe impairment after BCAS. PA endothelial function and structure were assessed by pressure myography. BCAS impaired endothelial function in PAs, as evidenced by reduced dilation to carbachol. Addition of nitric oxide synthase and cyclooxygenase inhibitors did not change carbachol-mediated dilation in either group. Inhibiting CYP epoxygenase, the enzyme that produces epoxyeicosatrienoic acid (EETs), a key determinant of endothelium-derived hyperpolarizing factor (EDHF)-mediated dilation, abolished dilation in PAs from Sham rats, but had no effect in PAs from BCAS rats. Expression of TRPV4 channels, a target for EETs, was decreased and maximal dilation to a TRPV4 agonist was attenuated after BCAS. Together these data suggest that EET-mediated dilation is impaired in PAs after BCAS. Thus impaired endothelium-dependent dilation in the PAs may be one of the contributing factors to the cognitive impairment observed after BCAS.
慢性脑灌注不足是认知障碍的一个危险因素。双侧颈动脉狭窄（BCAS）引起的通过颈总动脉的血流减少是慢性脑灌注不足的一种生理相关模型。我们假设，20周龄的Wistar-Kyoto（WKY）大鼠发生BCAS会损害认知功能，并导致实质小动脉（PA）的内皮依赖性舒张功能降低和向外重塑。BCAS 8周后，短期记忆和空间辨别能力均受损。脑血管储备能力的体内评估显示，BCAS后有严重损害。通过压力肌动描记法评估PA的内皮功能和结构。BCAS损害了PA的内皮功能，这可通过对卡巴胆碱的舒张反应降低来证明。添加一氧化氮合酶和环氧化酶抑制剂在两组中均未改变卡巴胆碱介导的舒张反应。抑制细胞色素P450环氧化酶（产生环氧二十碳三烯酸（EETs）的酶，EETs是内皮源性超极化因子（EDHF）介导的舒张反应的关键决定因素）可消除假手术组大鼠PA的舒张反应，但对BCAS组大鼠的PA无影响。BCAS后，EETs的靶点TRPV4通道的表达降低，对TRPV4激动剂的最大舒张反应减弱。这些数据共同表明，BCAS后PA中EET介导的舒张反应受损。因此，PA中内皮依赖性舒张功能受损可能是BCAS后观察到的认知障碍的促成因素之一。
