Cerebral Myogenic Reactivity and Blood Flow in Type 2 Diabetic Rats: Role of Peroxynitrite in Hypoxia-Mediated Loss of Myogenic Tone
Cerebral Myogenic Reactivity and Blood Flow in Type 2 Diabetic Rats: Role of Peroxynitrite in Hypoxia-Mediated Loss of Myogenic Tone
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DOI：
10.1124/jpet.111.191296
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发表时间：
2012-08-01
影响因子：
3.5
通讯作者：
Ergul, Adviye
中科院分区：
文献类型：
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作者：
Kelly-Cobbs, Aisha I.;Prakash, Roshini;Ergul, Adviye
脑血管功能失调，最终导致脑血流量（CBF）失调，可能导致并发症，如中风和糖尿病认知能力下降。我们假设1）糖尿病介导的神经血管和肌源性功能障碍损害CBF和2）在缺氧条件下，糖尿病大鼠的脑血管由于过氧亚硝酸盐（ONOO-）介导的血管平滑肌（VSM）肌动蛋白的硝化而失去肌源性。在10- 12周的对照组和2型糖尿病Goto-Kakizaki大鼠中，分别评估了功能性充血、血管在神经元刺激后扩张的能力和分离的大脑中动脉（MCA）的肌源性张力作为神经血管和肌源性功能的指标。此外，在常氧和缺氧[氧葡萄糖剥夺（OGD）]条件下，在有和没有ONOO-分解催化剂5，10，15，20-四（4-磺酸基苯基）三硝基铁（III）氯化物（FeTPPs）的情况下，测量MCA的生肌行为、硝基酪氨酸（NY）水平和VSM肌动蛋白含量。糖尿病患者肌源性张力的百分比较高，并且在较高压力下发生强制扩张。功能性充血受损。与这些发现一致，糖尿病患者的基线CBF较低。OGD降低了两组中肌源性张力的百分比，而FeTPPs仅在糖尿病中恢复。OGD增加VSM NY在两组中，虽然FeTPPs恢复基础水平，它并没有纠正减少丝状/球状（F/G）肌动蛋白的比例。VSM ONOO-水平的急性改变可能导致缺氧性肌源性功能障碍，但这不能仅仅通过肌动蛋白硝化导致的F/G肌动蛋白比率降低来解释，并且机制在对照组和糖尿病动物之间可能不同。我们的研究结果还表明，糖尿病改变了脑血管的能力，调节基础和缺氧条件下的CBF。
Dysregulation of cerebral vascular function and, ultimately, cerebral blood flow (CBF) may contribute to complications such as stroke and cognitive decline in diabetes. We hypothesized that 1) diabetes-mediated neurovascular and myogenic dysfunction impairs CBF and 2) under hypoxic conditions, cerebral vessels from diabetic rats lose myogenic properties because of peroxynitrite (ONOO-)-mediated nitration of vascular smooth muscle (VSM) actin. Functional hyperemia, the ability of blood vessels to dilate upon neuronal stimulation, and myogenic tone of isolated middle cerebral arteries (MCAs) were assessed as indices of neurovascular and myogenic function, respectively, in 10- to 12-week control and type 2 diabetic Goto-Kakizaki rats. In addition, myogenic behavior of MCAs, nitrotyrosine (NY) levels, and VSM actin content were measured under normoxic and hypoxic [oxygen glucose deprivation (OGD)] conditions with and without the ONOO- decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl) prophyrinato iron (III), chloride (FeTPPs). The percentage of myogenic tone was higher in diabetes, and forced dilation occurred at higher pressures. Functional hyperemia was impaired. Consistent with these findings, baseline CBF was lower in diabetes. OGD reduced the percentage of myogenic tone in both groups, and FeTPPs restored it only in diabetes. OGD increased VSM NY in both groups, and although FeTPPs restored basal levels, it did not correct the reduced filamentous/globular (F/G) actin ratio. Acute alterations in VSM ONOO- levels may contribute to hypoxic myogenic dysfunction, but this cannot be solely explained by the decreased F/G actin ratio due to actin nitration, and mechanisms may differ between control and diabetic animals. Our findings also demonstrate that diabetes alters the ability of cerebral vessels to regulate CBF under basal and hypoxic conditions.