Cardiovascular and renal regulation by the angiotensin type 2 receptor -: The AT2 receptor comes of age
Cardiovascular and renal regulation by the angiotensin type 2 receptor -: The AT2 receptor comes of age
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DOI：
10.1161/01.hyp.0000159192.93968.8f
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发表时间：
2005-05-01
期刊：
影响因子：
8.3
通讯作者：
Carey, RM
中科院分区：
文献类型：
--
作者：
Carey, RM
正常妊娠伴随着AT 2受体表达的增强，13很可能AT 2受体介导妊娠中的反调节血管舒张。如果是这样，那么AT 2受体表达和功能的异常是妊娠高血压综合征（先兆子痫）血管收缩的候选者。AT 2受体在流动条件下扩张肠系膜动脉段。14在存在AT 1受体阻断剂的情况下，Ang II通过内皮AT 2受体扩张这些血管。BK-B2受体阻断剂基本上抑制了这种反应，与野生型（WT）对照组相比，激肽原缺陷型Brown Norway Katholick大鼠中AT 2受体介导的血管舒张显著减少。14这些研究表明，AT 2受体通过肠系膜阻力血管中局部BK的产生以流量依赖性方式介导血管舒张。这些观察结果表明，血流增加引起的切应力可能在AT 2受体介导的血管舒张中很重要。类似地，Bergaya等人15表明，为了观察血管激肽释放酶/激肽系统对流量依赖性扩张的贡献，需要功能性AT 2受体。在WT小鼠中，用PD抑制AT 2受体降低了血流诱导的扩张，但在缺乏组织激肽释放酶的小鼠中没有。15在这些研究中，BK-B2受体拮抗剂艾替班特减少了WT小鼠对血流的血管舒张反应，但在缺乏AT 2受体的小鼠中没有。总之，这一新的信息强烈表明，阻力微血管是一个主要的网站AT 2受体的行动。然而，在过去一年中积累的证据也证明了AT 2受体在大容量血管中的作用。Yayama等人16通过肾上腹主动脉结扎术检测了压力超负荷大鼠胸主动脉中的AT 2受体表达。在结扎后4、7、14和28天，压力超负荷主动脉中AT 2受体mRNA表达上调3倍。在压力超载的血管，血管紧张素II收缩反应被废除，但恢复到控制水平的AT 2受体拮抗剂PD。去除内皮细胞抵消了之前观察到的假手术对照组和压力超负荷组血管紧张素II反应性的差异。因此，大容量血管的压力超负荷上调AT 2受体表达，这似乎限制了Ang II介导的血管收缩。由于在该模型中肾灌注压和血流量降低，内源性肾素-血管紧张素系统被激活，这可能诱导AT 2受体表达和功能增加。在这方面，本研究发现，压力诱导的AT 2受体表达依赖于AT 1受体的Ang II激活。因此，可以建立反调节正反馈回路，其中AT 1受体诱导的血管收缩被AT 2受体上调和随后的血管舒张自动抵消。在压力超负荷模型中，AT 2受体诱导的扩张机制是BK依赖性的，因为在小鼠中，PD或艾替班特可恢复收缩反应。17 Ang II引起主动脉cGMP增加9倍，PD或艾替班特消除了这种增加。功能性血管扩张剂AT 2受体也已在胎儿主动脉中得到证实，其中AT 2受体表达极高。这些发现在病理生理学上可能很重要，因为在某些疾病状态下，正常的反调节AT 2受体上调可能变得迟缓或缓慢，导致血管收缩无法减轻。
normal pregnancy is accompanied by enhancement of AT2 receptor expression, 13 it is likely that the AT2 receptor mediates counter-regulatory vasodilation in pregnancy. If this is so, then abnormalities in AT2 receptor expression and function are candidates for vasoconstriction in pregnancyinduced hypertension (preeclampsia). The AT2 receptor dilates mesenteric arterial segments under flow conditions. 14 In the presence of AT1 receptor blockade, Ang II dilated these vessels via endothelial AT2 receptors. BK-B2 receptor blockade substantially inhibited this response, and AT2 receptor-mediated vasodilation was markedly reduced in kininogen-deficient Brown Norway Katholick rats compared with wild-type (WT) controls. 14 These studies demonstrate that the AT2 receptor mediates vasodilation via local BK production in mesenteric resistance vessels in a flow-dependent manner. These observations suggest that shear stress caused by increased blood flow maybe important in AT2 receptor-mediated vasodilation. Similarly, Bergaya et al15 showed that to observe the contribution of the vascular kallikrein/kinin system to flowdependant dilation, functional AT2 receptors are required. AT2 receptor inhibition with PD decreased flow-induced dilation in WT mice, but not in mice lacking tissue kallikrein. 15 In these studies, the BK-B2 receptor antagonist icatibant reduced the vasodilatory response to flow in WT mice, but not in mice lacking the AT2 receptor. Taken together, this new information strongly suggests that resistance microvessels are a major site of AT2 receptor action. However, evidence accumulated during the past year also documents a role of AT2 receptors in large capacitance vessels. Yayama et al16 tested AT2 receptor expression in the rat thoracic aorta subjected to pressure-overload by means of suprarenal abdominal aortic banding. There was a 3-fold upregulation of AT2 receptor mRNA in the pressureoverloaded aorta 4, 7, 14, and 28 days after banding. In the pressure-overloaded vessels, Ang II constrictor responses were abrogated but were restored to control levels by AT2 receptor antagonist PD. Removal of the endothelium nullified the differences in Ang II responsiveness previously observed between sham control and pressure-overloaded aortae. Therefore, pressure-overload of large capacitance vessels upregulates AT2 receptor expression, which appears to limit Ang II-mediated vasoconstriction. Because renal perfusion pressure and blood flow were reduced in this model, the endogenous renin-angiotensin system was activated, which may have induced increased AT2 receptor expression and function. In this regard, this study found that pressure-induced AT2 receptor expression was dependent on Ang II activation of AT1 receptors. Thus, a counter-regulatory positive feedback loop may be established wherein AT1 receptor-induced vasoconstriction is automatically counterbalanced by AT2 receptor upregulation and consequent vasodilation. The mechanism of AT2 receptor-induced dilation in the pressure-overload model is BK-dependent, because the contractile response was restored with PD or icatibant in mice. 17 Ang II invoked a 9-fold increase in aortic cGMP that was abolished by either PD or icatibant. Functional vasodilator AT2 receptors also have been demonstrated in the fetal aorta, where AT2 receptor expression is extremely high. 18 These findings may be important in pathophysiology, because normal counter-regulatory upregulation of the AT2 receptor in certain disease states may be rendered sluggish or inoperative, lending to unmitigated vasoconstriction.Two studies during the past year have clarified AT2 …