Rapamycin reversal of VEGF-C-driven lymphatic anomalies in the respiratory tract
Rapamycin reversal of VEGF-C-driven lymphatic anomalies in the respiratory tract
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DOI：
10.1172/jci.insight.90103
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发表时间：
2017-08-17
期刊：
影响因子：
8
通讯作者：
McDonald, Donald M.
中科院分区：
文献类型：
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作者：
Baluk, Peter;Yao, Li-Chin;McDonald, Donald M.
淋巴管畸形是一种严重但知之甚少的疾病，对治疗提出了挑战。这项研究的目的是比较诱导异常淋巴管消退的策略，并探索潜在的机制。采用强力霉素调控肺淋巴管扩张的CCSP-RTTA/Teto-VEGF-C小鼠作为肺淋巴管扩张模型。停用多西环素后，血管内皮生长因子-C表达恢复正常，但淋巴管扩张至少持续9个月。抑制VEGFR-2/VEGFR-3信号、Notch、β-肾上腺素能受体、自噬和抗炎激素对淋巴管扩张症的数量和严重程度没有明显影响。然而，雷帕霉素对mTOR的抑制在7天内减少了76%的淋巴管扩张，而不影响正常淋巴管。雷帕霉素与其他药物联合给药并不能提高疗效。在预防试验中，雷帕霉素抑制了血管内皮生长因子-C驱动的mTOR磷酸化和淋巴管内皮细胞的萌发和增殖。然而，在逆转试验中，在已建立的淋巴管扩张症中没有淋巴管内皮细胞的增殖被阻断，雷帕霉素也没有增加caspase依赖的细胞凋亡。然而，雷帕霉素有效地抑制了Prox1和VEGFR-3。这些实验表明，淋巴管扩张症非常抗退，但对雷帕霉素有反应，雷帕霉素能迅速减少异常淋巴管并使其正常化，而不影响正常淋巴管。
Lymphatic malformations are serious but poorly understood conditions that present therapeutic challenges. The goal of this study was to compare strategies for inducing regression of abnormal lymphatics and explore underlying mechanisms. CCSP-rtTA/tetO-VEGF-C mice, in which doxycycline regulates VEGF-C expression in the airway epithelium, were used as a model of pulmonary lymphangiectasia. After doxycycline was stopped, VEGF-C expression returned to normal, but lymphangiectasia persisted for at least 9 months. Inhibition of VEGFR-2/VEGFR-3 signaling, Notch, beta-adrenergic receptors, or autophagy and antiinflammatory steroids had no noticeable effect on the amount or severity of lymphangiectasia. However, rapamycin inhibition of mTOR reduced lymphangiectasia by 76% within 7 days without affecting normal lymphatics. Efficacy of rapamycin was not increased by coadministration with the other agents. In prevention trials, rapamycin suppressed VEGF-C-driven mTOR phosphorylation and lymphatic endothelial cell sprouting and proliferation. However, in reversal trials, no lymphatic endothelial cell proliferation was present to block in established lymphangiectasia, and rapamycin did not increase caspase-dependent apoptosis. However, rapamycin potently suppressed Prox1 and VEGFR-3. These experiments revealed that lymphangiectasia is remarkably resistant to regression but is responsive to rapamycin, which rapidly reduces and normalizes the abnormal lymphatics without affecting normal lymphatics.