Central cardiovascular circuits contribute to the neurovascular dysfunction in angiotensin II hypertension.
Central cardiovascular circuits contribute to the neurovascular dysfunction in angiotensin II hypertension.
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DOI：
10.1523/jneurosci.6262-11.2012
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发表时间：
2012-04-04
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影响因子：
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通讯作者：
Iadecola C
中科院分区：
文献类型：
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作者：
Capone C;Faraco G;Peterson JR;Coleman C;Anrather J;Milner TA;Pickel VM;Davisson RL;Iadecola C
高血压是中风和痴呆的一个重要危险因素，对大脑及其血管有破坏性影响。特别是，高血压改变了重要的脑血管控制机制，将神经活动与脑灌注联系起来。在缓慢发展的高血压的实验模型中，穹窿下器官（SFO）（前脑室周器官之一）中的自由基信号传导对于激素释放和交感神经激活驱动动脉压升高是至关重要的。然而，这一中枢机制对高血压引起的脑血管改变的作用仍不确定。我们测试的假设，自由基的产生在SFO参与高血压引起的脑血管调节的改变。在慢性降压剂量的血管紧张素II（AngII）引起的渐进性高血压的小鼠模型中，通过过度表达CuZnSOD抑制SFO中的自由基，防止了高血压引起的体感皮层神经血管耦联和内皮依赖性反应的改变。SFO通过两条信号通路介导功能障碍。一个涉及SFO依赖的室旁下丘脑核的激活，血浆加压素的升高，脑阻力小动脉中内皮素-1的上调和内皮素A型受体的激活。另一个途径依赖于血管紧张素II激活脑血管紧张素II AT 1受体。这两种途径通过诱导血管氧化应激介导血管功能障碍。研究结果首次涉及SFO及其传出下丘脑通路在血管紧张素II诱导的脑血管变化，并确定加压素和内皮素-1作为潜在的治疗靶点，以抵消高血压对大脑的破坏性影响。
Hypertension, a powerful risk factor for stroke and dementia, has damaging effects on the brain and its vessels. In particular, hypertension alters vital cerebrovascular control mechanisms linking neural activity to cerebral perfusion. In experimental models of slow-developing hypertension, free radical signaling in the subfornical organ (SFO), one of the forebrain circumventricular organs, is critical for the hormonal release and sympathetic activation driving the elevation in arterial pressure. However, the contribution of this central mechanism to the cerebrovascular alterations induced by hypertension remains uncertain. We tested the hypothesis that free radical production in the SFO is involved in the alterations in cerebrovascular regulation produced by hypertension. In a mouse model of gradual hypertension induced by chronic administration of sub-pressor doses of angiotensin II (AngII), suppression of free radicals in the SFO by overexpression of CuZnSOD prevented the alteration in neurovascular coupling and endothelium-dependent responses in somatosensory cortex induced by hypertension. The SFO mediates the dysfunction via two signaling pathways. One involves SFO-dependent activation of the paraventricular hypothalamic nucleus, elevations in plasma vasopressin, upregulation of endothelin-1 in cerebral resistance arterioles and activation of endothelin type A receptors. The other pathway depends on activation of cerebrovascular AngII AT1 receptors by AngII. Both pathways mediate vasomotor dysfunction by inducing vascular oxidative stress. The findings implicate for the first time the SFO and its efferent hypothalamic pathways in the cerebrovascular alterations induced by AngII, and identify vasopressin and endothelin-1 as potential therapeutic targets to counteract the devastating effects of hypertension on the brain.