Aldosterone enhances ischemia-induced neovascularization through angiotensin II-dependent pathway
Aldosterone enhances ischemia-induced neovascularization through angiotensin II-dependent pathway
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DOI：
10.1161/01.cir.0000127112.36796.9b
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发表时间：
2004-04-27
期刊：
影响因子：
37.8
通讯作者：
Silvestre, JS
中科院分区：
文献类型：
--
作者：
Michel, F;Ambroisine, ML;Silvestre, JS
背景-我们分析了醛固酮在缺血诱导的新生血管中的作用以及血管紧张素II(Ang II)信号转导途径在这一效应中的参与。方法和结果：用或不用醛固酮(4.5µg/d)、醛固酮+螺内酯(醛固酮受体阻滞剂，每天20 mg/kg)或醛固酮+valsartan(血管紧张素1型[AT(1)]受体阻滞剂，每天20 mg/kg)处理或不处理均可诱导小鼠脑缺血。21天后，通过微血管造影、毛细血管密度测量和激光多普勒血流成像对新生血管进行评估。用Western印迹法检测大鼠后肢血管内皮生长因子(VEGF)的蛋白水平。用半定量逆转录聚合酶链式反应检测肾素-血管紧张素系统各组分的mRNA水平。与对照组相比，接受醛固酮治疗的小鼠缺血/非缺血小腿的血管造影评分、毛细血管数量和足部血流灌注分别提高了1.4倍、1.5倍和1.4倍(P<；0.05)。醛固酮促血管生成作用与血管内皮生长因子蛋白含量增加2.3倍相关(P<；0.05)。使用螺内酯或中和的血管内皮生长因子抗体的治疗阻碍了醛固酮的促血管生成作用(P<；0.05与醛固酮治疗的小鼠相比)。有趣的是，AT(1)受体阻断完全阻断了醛固酮促血管生成的作用，强调了Ang II相关途径参与了醛固酮诱导的血管生长。在这一观点中，给予醛固酮治疗的小鼠血管紧张素原mRNA含量是对照组的2.2倍(P<；0.05)，而肾素、血管紧张素转换酶和AT1受体亚型的含量不受影响。与对照组相比，醛固酮处理组血管紧张素Ⅱ受体基因的含量减少了2倍(P<；0.05)，提示醛固酮可能通过激活血管紧张素Ⅱ信号转导血管生成途径。结论：本研究首次表明，在缺血状态下，醛固酮通过激活血管紧张素Ⅱ信号通路增加血管新生。
Background-We analyzed the role of aldosterone in ischemia-induced neovascularization and the involvement of angiotensin II (Ang II) signaling in this effect.Methods and Results-Ischemia was induced by right femoral artery ligature in mice treated or not with aldosterone (4.5 mug/day), aldosterone plus spironolactone (aldosterone receptor blocker; 20 mg/kg per day), or aldosterone plus valsartan (angiotensin type 1 [AT(1)] receptor blocker; 20 mg/kg per day). After 21 days, neovascularization was evaluated by microangiography, capillary density measurement, and laser-Doppler perfusion imaging. Protein level of vascular endothelial growth factor (VEGF) was determined by Western blot analysis in hindlimbs. mRNA levels of renin-angiotensin system components were also assessed by semiquantitative reverse transcription-polymerase chain reaction. Angiographic score, capillary number, and foot perfusion were improved in ischemic/nonischemic leg ratio by 1.4-, 1.5-, and 1.4-fold, respectively, in aldosterone-treated mice compared with controls (P < 0.05). Aldosterone proangiogenic effect was associated with 2.3-fold increase in VEGF protein content (P < 0.05). Treatments with spironolactone or with neutralizing VEGF antibody hampered the proangiogenic effect of aldosterone (P < 0.05 versus aldosterone-treated mice). Interestingly, AT(1) receptor blockade completely abrogated the aldosterone proangiogenic effect, emphasizing the involvement of Ang II-related pathway in aldosterone-induced vessel growth. In this view, angiotensinogen mRNA content was 2.2-fold increased in aldosterone-treated mice in reference to controls (P < 0.05), whereas that of renin, angiotensin-converting enzyme, and AT1 receptor subtype was unaffected. Aldosterone treatment also decreased AT(2) mRNA content by 2-fold (P < 0.05 versus controls), suggesting that aldosterone may switch the Ang II pathway toward activation of vessel growth.Conclusions-This study shows for the first time that aldosterone increases neovascularization in the setting of ischemia through activation of Ang II signaling.