Endothelium-restricted overexpression of human endothelin-1 causes vascular remodeling and endothelial dysfunction
Endothelium-restricted overexpression of human endothelin-1 causes vascular remodeling and endothelial dysfunction
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DOI：
10.1161/01.cir.0000144462.08345.b9
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发表时间：
2004-10-12
期刊：
影响因子：
37.8
通讯作者：
Schiffrin, EL
中科院分区：
文献类型：
--
作者：
Amiri, F;Virdis, A;Schiffrin, EL
内皮素（ET）-1是一种强有力的血管收缩剂，在高血压和其他心血管疾病中促进血管重塑。内源性ET-1主要由血管内皮细胞产生。为了直接测试内皮衍生的ET-1在心血管病理生理学中的作用，我们通过使用Tie-2启动子在C57 BL/6 mice.Methods和Results-10周龄雄性C57 BL/6转基因（TG）和非转基因（野生型; WT）同窝仔中特异性靶向表达人preproET-1基因至内皮。TG小鼠的血管组织ET-1 mRNA和ET-1血浆水平比WT小鼠高3倍，但血压没有显著升高。尽管没有显着的血压升高，TG小鼠表现出显着的肥厚性重塑和氧化剂过量依赖性内皮功能障碍的阻力血管，改变ET-1和ET-3血管反应，并显着增加ETB的表达与WT同窝。此外，TG小鼠产生了显着更高的氧化应激，可能是通过增加的活性和表达的血管NAD（P）H氧化酶比他们的WT countermeasurement. Conclusions-在这个新的小鼠模型内皮限制的人preproET-1过表达，ET-1引起结构重塑和内皮功能障碍的阻力血管，符合直接的非血流动力学效应的ET-1对血管，至少部分通过激活血管NAD（P）H氧化酶。
Background-Endothelin (ET)-1 is a potent vasoconstrictor that contributes to vascular remodeling in hypertension and other cardiovascular diseases. Endogenous ET-1 is produced predominantly by vascular endothelial cells. To directly test the role of endothelium-derived ET-1 in cardiovascular pathophysiology, we specifically targeted expression of the human preproET-1 gene to the endothelium by using the Tie-2 promoter in C57BL/6 mice.Methods and Results-Ten-week-old male C57BL/6 transgenic (TG) and nontransgenic (wild type; WT) littermates were studied. TG mice exhibited 3-fold higher vascular tissue ET-1 mRNA and 7-fold higher ET-1 plasma levels than did WT mice but no significant elevation in blood pressure. Despite the absence of significant blood pressure elevation, TG mice exhibited marked hypertrophic remodeling and oxidant excess-dependent endothelial dysfunction of resistance vessels, altered ET-1 and ET-3 vascular responses, and significant increases in ETB expression compared with WT littermates. Moreover, TG mice generated significantly higher oxidative stress, possibly through increased activity and expression of vascular NAD(P)H oxidase than did their WT counterparts.Conclusions-In this new murine model of endothelium-restricted human preproET-1 overexpression, ET-1 caused structural remodeling and endothelial dysfunction of resistance vessels, consistent with a direct nonhemodynamic effect of ET-1 on the vasculature, at least in part through the activation of vascular NAD(P)H oxidase.