RATIONALE ENG (endoglin) is a coreceptor for BMP (bone morphogenetic protein) 9/10 and is strongly expressed in endothelial cells. Mutations in ENG lead to the inherited vascular disorder hereditary hemorrhagic telangiectasia characterized by local telangiectases and larger arteriovenous malformations (AVMs); but how ENG functions to regulate the adult vasculature is not understood. OBJECTIVE The goal of the work was to determine how ENG maintains vessel caliber in adult life to prevent AVM formation and thereby protect heart function. METHODS AND RESULTS Genetic depletion of endothelial Eng in adult mice led to a significant reduction in mean aortic blood pressure. There was no evidence of hemorrhage, anemia, or AVMs in major organs to explain the reduced aortic pressure. However, large AVMs developed in the peripheral vasculature intimately associated with the pelvic cartilaginous symphysis-a noncapsulated cartilage with a naturally high endogenous expression of VEGF (vascular endothelial growth factor). The increased blood flow through these peripheral AVMs explained the drop in aortic blood pressure and led to increased cardiac preload, and high stroke volumes, ultimately resulting in high-output heart failure. Development of pelvic AVMs in this region of high VEGF expression occurred because loss of ENG in endothelial cells leads to increased sensitivity to VEGF and a hyperproliferative response. Development of AVMs and associated progression to high-output heart failure in the absence of endothelial ENG was attenuated by targeting VEGF signaling with an anti-VEGFR2 (VEGF receptor 2) antibody. CONCLUSIONS ENG promotes the normal balance of VEGF signaling in quiescent endothelial cells to maintain vessel caliber-an essential function in conditions of increased VEGF expression such as local hypoxia or inflammation. In the absence of endothelial ENG, increased sensitivity to VEGF drives abnormal endothelial proliferation in local regions of high VEGF expression, leading to AVM formation and a rapid injurious impact on heart function.

中文翻译：

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内皮内皮糖蛋白的缺失通过由 VEGF 信号驱动的外周动静脉分流促进高输出心力衰竭。

RATIONALE ENG（endoglin）是 BMP（骨形态发生蛋白）9/10 的辅助受体，在内皮细胞中强烈表达。ENG突变导致遗传性血管疾病遗传性出血性毛细血管扩张症，其特征是局部毛细血管扩张和更大的动静脉畸形（AVM）；但 ENG 如何发挥调节成人脉管系统的作用尚不清楚。目的 这项工作的目的是确定 ENG 如何在成年生活中保持血管口径，以防止 AVM 形成，从而保护心脏功能。方法和结果 成年小鼠内皮 Eng 的基因缺失导致平均主动脉血压显着降低。没有证据表明主要器官有出血、贫血或 AVM 来解释主动脉压降低。然而，在与盆腔软骨联合密切相关的外周脉管系统中形成的大型 AVM - 一种非包膜软骨，具有天然高内源性 VEGF（血管内皮生长因子）表达。通过这些外周 AVM 的血流量增加解释了主动脉血压下降并导致心脏前负荷增加和每搏输出量增加，最终导致高输出心力衰竭。由于内皮细胞中 ENG 的缺失导致对 VEGF 的敏感性增加和过度增殖反应，因此在该 VEGF 高表达区域发生盆腔 AVM。通过用抗 VEGFR2（VEGF 受体 2）抗体靶向 VEGF 信号传导减弱了 AVM 的发展和在没有内皮 ENG 的情况下向高输出心力衰竭的相关进展。结论 ENG 促进静止内皮细胞中 VEGF 信号的正常平衡，以维持血管口径——这是在 VEGF 表达增加的情况下（例如局部缺氧或炎症）的基本功能。在没有内皮 ENG 的情况下，对 VEGF 的敏感性增加会驱动高 VEGF 表达的局部区域的异常内皮增殖，导致 AVM 形成和对心脏功能的快速伤害性影响。