Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis
Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis
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DOI：
10.1172/jci66549
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发表时间：
2013-08-01
影响因子：
15.9
通讯作者：
Kupatt, Christian
中科院分区：
文献类型：
--
作者：
Ziegler, Tilman;Horstkotte, Jan;Kupatt, Christian
尽管心输出量增加，但脓毒性休克的特征是血管通透性增加和低血压。许多血管活性细胞因子在脓毒症期间上调，包括血管生成素 2 (ANG2)，它会增加血管通透性。在这里，我们报道了在内皮细胞中诱导过度表达 ANG2 的小鼠出现了脓毒症样血流动力学改变，包括全身性低血压、心输出量增加和扩张性心肌病。相反，心肌细胞限制性 ANG2 过度表达的小鼠未能发生血流动力学改变。有趣的是，通过静脉注射转导血管生成素1（一种拮抗ANG2的TIE2配体）的cDNA的腺相关病毒（AAV）或编码PDGFB（一种周细胞趋化剂）的AAV，可以逆转与ANG2内皮特异性过度表达和毛细血管相关周细胞损失相关的血流动力学改变。为了确认 ANG2 在脓毒症中的作用，我们进行了腹腔注射。将 LPS 注射到 C57BL/6J 小鼠体内，小鼠迅速出现低血压、急性周细胞丢失和血管通透性增加。重要的是，ANG2 抗体治疗减弱了 LPS 诱导的血流动力学改变，并将 36 小时死亡率从 95% 降低至 61%。这些数据表明ANG2介导的微血管崩解导致脓毒性休克，并且脓毒症期间ANG2/TIE2相互作用的抑制是潜在的治疗靶点。
Septic shock is characterized by increased vascular permeability and hypotension despite increased cardiac output. Numerous vasoactive cytokines are upregulated during sepsis, including angiopoietin 2 (ANG2), which increases vascular permeability. Here we report that mice engineered to inducibly overexpress ANG2 in the endothelium developed sepsis-like hemodynamic alterations, including systemic hypotension, increased cardiac output, and dilatory cardiomyopathy. Conversely, mice with carcliomyocyte-restricted ANG2 overexpression failed to develop hemodynamic alterations. Interestingly, the hemodynamic alterations associated with endothelial-specific overexpression of ANG2 and the loss of capillary-associated pericytes were reversed by intravenous injections of adeno-associated viruses (AAVs) transducing cDNA for angiopoietin 1, a TIE2 ligand that antagonizes ANG2, or AAVs encoding PDGFB, a chemoattractant for pericytes. To confirm the role of ANG2 in sepsis, we i.p. injected LPS into C57BL/6J mice, which rapidly developed hypotension, acute pericyte loss, and increased vascular permeability. Importantly, ANG2 antibody treatment attenuated LPS-induced hemodynamic alterations and reduced the mortality rate at 36 hours from 95% to 61%. These data indicate that ANG2-mediated microvascular disintegration contributes to septic shock and that inhibition of the ANG2/TIE2 interaction during sepsis is a potential therapeutic target.