Department of Pharmacology and Toxicology, Michigan State University , East Lansing, Michigan.
Am J Physiol Heart Circ Physiol. 2018 Jan 1;314(1):H122-H130. doi: 10.1152/ajpheart.00638.2016. Epub 2017 Aug 25.
Hypertension is a leading risk factor for vascular cognitive impairment and is strongly associated with carotid artery stenosis. In normotensive rats, chronic cerebral hypoperfusion induced by bilateral common carotid artery stenosis (BCAS) leads to cognitive impairment that is associated with impaired endothelium-dependent dilation in parenchymal arterioles (PAs). The aim of this study was to assess the effects of BCAS on PA function and structure in stroke-prone spontaneously hypertensive rats, a model of human essential hypertension. Understanding the effects of hypoperfusion on PAs in a hypertensive model could lead to the identification of therapeutic targets for cognitive decline in a model that reflects the at-risk population. We hypothesized that BCAS would impair endothelium-dependent dilation in PAs and induce artery remodeling compared with sham rats. PAs from BCAS rats had endothelial dysfunction, as assessed using pressure myography. Inhibition of nitric oxide and prostaglandin production had no effect on PA dilation in sham or BCAS rats. Surprisingly, inhibition of epoxyeicosatrienoic acid production increased dilation in PAs from BCAS rats but not from sham rats. Similar results were observed in the presence of inhibitors for all three dilatory pathways, suggesting that epoxygenase inhibition may have restored a nitric oxide/prostaglandin-independent dilatory pathway in PAs from BCAS rats. PAs from BCAS rats underwent remodeling with a reduced wall thickness. These data suggest that marked endothelial dysfunction in PAs from stroke-prone spontaneously hypertensive rats with BCAS may be associated with the development of vascular cognitive impairment. NEW & NOTEWORTHY The present study assessed the structure and function of parenchymal arterioles in a model of chronic cerebral hypoperfusion and hypertension, both of which are risk factors for cognitive impairment. We observed that impaired dilation and artery remodeling in parenchymal arterioles and abolished cerebrovascular reserve capacity may mediate cognitive deficits.
高血压是血管性认知障碍的主要危险因素，与颈动脉狭窄密切相关。在正常血压大鼠中，双侧颈总动脉狭窄（BCAS）引起的慢性脑灌注不足导致认知障碍，与实质小动脉（PA）内皮依赖性扩张受损有关。本研究旨在评估 BCAS 对易发生中风的自发性高血压大鼠（一种人类原发性高血压模型）PA 功能和结构的影响。了解灌注不足对高血压模型中 PA 的影响，可能会确定反映高危人群认知能力下降的治疗靶点。我们假设 BCAS 会损害 PA 的内皮依赖性扩张，并与假手术大鼠相比诱导动脉重塑。通过压力描记法评估，BCAS 大鼠的 PA 存在内皮功能障碍。抑制一氧化氮和前列腺素的产生对 sham 或 BCAS 大鼠的 PA 扩张均无影响。令人惊讶的是，环氧合酶代谢产物抑制剂增加了 BCAS 大鼠而不是 sham 大鼠的 PA 扩张。在三种扩张途径的抑制剂存在下观察到类似的结果，表明环氧合酶抑制可能恢复了 BCAS 大鼠 PA 中一氧化氮/前列腺素非依赖性扩张途径。BCAS 大鼠的 PA 发生了重塑，壁厚度减小。这些数据表明，BCAS 易发生中风的自发性高血压大鼠的 PA 中明显的内皮功能障碍可能与血管性认知障碍的发展有关。
本研究评估了慢性脑灌注不足和高血压模型中实质小动脉的结构和功能，这两者都是认知障碍的危险因素。我们观察到，实质小动脉扩张受损和动脉重塑以及脑血管储备能力的丧失可能介导认知缺陷。
