Vascular endothelial cell-derived endothelin-1 mediates vascular inflammation and neointima formation following blood flow cessation
Vascular endothelial cell-derived endothelin-1 mediates vascular inflammation and neointima formation following blood flow cessation
复制标题
DOI：
10.1093/cvr/cvp026
复制
发表时间：
2009-04-01
影响因子：
10.8
通讯作者：
Hirata, Ken-ichi
中科院分区：
文献类型：
--
作者：
Anggrahini, Dyah W.;Emoto, Noriaki;Hirata, Ken-ichi
尽管内皮素-1(ET-1)被认为在新生内膜形成和动脉粥样硬化的发病机制中起作用，但某些类型的细胞来源的ET-1在本病中的单独作用尚不清楚。在这项研究中，我们利用血管内皮细胞ET-1基因敲除[ET-1(f/f)；Tie2-Cre(+)]小鼠来确定血管内皮细胞ET-1在血管炎症和新生内膜形成中的作用。12周龄雄性ET-1(f/f)、Tie2-Cre(+)小鼠(n=35)和野生型(WT)小鼠(n=34)完全结扎左侧颈动脉诱导内膜增生。干预后，与WT小鼠相比，ET-1(f/f)；Tie2-Cre(+)小鼠的新生内膜形成减少，与血压差异无关。这种减少与炎症细胞向血管壁募集的减少有关，并伴随着内皮细胞黏附分子和趋化因子表达水平的降低以及血管平滑肌细胞增殖的减少。我们的研究结果为血管内皮细胞ET-1除了促进血管收缩和细胞增殖之外，在介导血管损伤后的血管炎症和新生内膜形成中的作用提供了直接的证据。此外，这项研究提出了一种有效设计ET受体拮抗剂的策略，通过靶向抑制血管内皮细胞中的ET-1信号转导。
Although endothelin-1 (ET-1) has been suggested to contribute to the pathogenesis of neointima formation and atherosclerosis, the individual roles of ET-1 derived from certain cell types in this disease remain unclear. In this study, we determined the role of vascular endothelial ET-1 on vascular inflammation and neointima formation using vascular endothelial ET-1-knockout [ET-1(f/f); Tie2-Cre (+)] mice.Intimal hyperplasia was induced by complete ligation of the left carotid artery in 12-week-old male ET-1(f/f);Tie2-Cre (+) mice (n = 35) and the wild-type (WT) littermates (n = 34). Following this intervention, neointima formation was reduced in ET-1(f/f);Tie2-Cre (+) mice compared with the WT mice, independent of the difference in blood pressure. This reduction was associated with a decrease in inflammatory cell recruitment to the vessel wall, which was accompanied by reduced expression levels of endothelial adhesion molecules as well as chemokines and a decrease in vascular smooth muscle cell proliferation.The results of our study provide direct evidence for the role of vascular endothelial ET-1 in mediating vascular inflammation and neointima formation following vascular injury in addition to promoting vasoconstriction and cell proliferation. Furthermore, this study suggests a strategy for the efficient design of ET receptor antagonists with targeted inhibition of ET-1 signalling in vascular endothelial cells.