Endothelium-dependent impairments to cerebral vascular reactivity with type 2 diabetes mellitus in the Goto-Kakizaki rat
Endothelium-dependent impairments to cerebral vascular reactivity with type 2 diabetes mellitus in the Goto-Kakizaki rat
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DOI：
10.1152/ajpregu.00088.2019
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发表时间：
2019-07-01
影响因子：
2.8
通讯作者：
Frisbee, Jefferson C.
中科院分区：
文献类型：
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作者：
Halvorson, Brayden D.;Whitehead, Shawn N.;Frisbee, Jefferson C.
2型糖尿病(T2 DM)是一种与脑血管疾病风险增加相关的流行病理。我们检测了雄性Goto-Kakizaki大鼠(GK；类似于17周大鼠)和对照Wistar京都大鼠(WKY)的体外大脑中动脉(MCA)的壁力学和血管反应性，以验证GK中的糖尿病环境在没有肥胖和其他并发症的情况下会导致内皮功能障碍和血管张力调节受损的假说。由于一氧化氮生物利用度降低和花生四烯酸代谢改变，GK组和WKY组MCA在乙酰胆碱刺激和缺氧后的扩张被钝化，而对5-羟色胺的肌源性激活和收缩反应没有变化。大脑中动脉壁膨胀性和横截面积在GK和WKY之间没有差异，这表明壁力学在这个年龄段没有变化，这是因为确定MCA对硝普钠的扩张也是完整的。使用体外主动脉环作为生物测定，MCA中测定的血管反应性改变与GK的动脉节段的松弛反应平行，而血管活性代谢物产生的测量表明一氧化氮和前列环素的生物利用度丧失，而乙酰甲胆碱刺激和缺氧增加了血栓素A(2)的产生。这些结果提示T2 DM时GK患者MCA的内皮依赖性扩张剂反应性受损，并且这种损害与糖尿病的促氧化/促炎状态的发生有关。血管损伤对内皮功能的限制，在这个年龄和发育阶段，提供了对多病的严重性的洞察，其中T2 DM只是其中一个组成部分。
Type 2 diabetes mellitus (T2DM) is a prevalent pathology associated with elevated cerebrovascular disease risk. We determined wall mechanics and vascular reactivity in ex vivo middle cerebral arteries (MCA) from male Goto-Kakizaki rats (GK; similar to 17 wk old) versus control Wistar Kyoto rats (WKY) to test the hypothesis that the diabetic environment in GK, in the absence of obesity and other comorbidities, leads to endothelial dysfunction and impaired vascular tone regulation. Dilation of MCA following challenge with acetylcholine and hypoxia was blunted in MCA from GK versus WKY, due to lower nitric oxide bioavailability and altered arachidonic acid metabolism, whereas myogenic activation and constrictor responses to serotonin were unchanged. MCA wall distensibility and cross-sectional area were not different between GK and WKY, suggesting that wall mechanics were unchanged at this age, supported by the determination that MCA dilation to sodium nitroprusside was also intact. With the use of ex vivo aortic rings as a bioassay, altered vascular reactivity determined in MCA was paralleled by relaxation responses in artery segments from GK, whereas measurements of vasoactive metabolite production indicated a loss of nitric oxide and prostacyclin bioavailability and an increased thromboxane A(2) production with both methacholine challenge and hypoxia. These results suggest that endothelium-dependent dilator reactivity of MCA in GK is impaired with T2DM, and that this impairment is associated with the genesis of a prooxidant/pro-inflammatory condition with diabetes mellitus. The restriction of vascular impairments to endothelial function only, at this age and development, provide insight into the severity of multimorbid conditions of which T2DM is only one constituent.