Pathological MAPK activation-mediated lymphatic basement membrane disruption causes lymphangiectasia that is treatable with ravoxertinib.
Pathological MAPK activation-mediated lymphatic basement membrane disruption causes lymphangiectasia that is treatable with ravoxertinib.
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DOI：
10.1172/jci.insight.153033
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发表时间：
2022-09-08
期刊：
影响因子：
8
通讯作者：
Trivedi, Chinmay M.
中科院分区：
文献类型：
--
作者：
Janardhan, Harish P.;Dresser, Karen;Hutchinson, Lloyd;Trivedi, Chinmay M.
淋巴管扩张症是一种淋巴管异常扩张，最早描述于17世纪，在年轻患者中经常与乳糜渗出、呼吸衰竭和高死亡率相关，但其潜在的分子发病机制和有效的治疗方法仍不清楚。在这里，我们确定了一个意想不到的因果关系之间的MAPK激活和有缺陷的发展，驱动淋巴管扩张的淋巴基底膜。来自被诊断患有淋巴管扩张症的患者的人类病理组织样品揭示了淋巴管内皮细胞内持续的MAPK活化。新生小鼠中内皮KRASG12D介导的持续MAPK激活引起严重的肺和肋间淋巴管扩张、乳糜在胸膜腔中的积累和完全致死。MAPK在小鼠脉管系统中的病理激活抑制了层粘连蛋白相互作用、胶原交联和锚定纤维形成所需的Nfatc1依赖性遗传程序，从而驱动淋巴基底膜的缺陷性发育。ravoxertinib（一种MAPK的药理学抑制剂）治疗可逆转Nfatc 1的核质定位、基底膜发育缺陷、淋巴管扩张和乳糜蓄积，最终改善内皮KRAS突变新生小鼠的生存期。这些结果揭示了有缺陷的淋巴基底膜组装和组成的主要原因胸部淋巴管扩张症，并提供了一个潜在的治疗。
Lymphangiectasia, an anomalous dilation of lymphatic vessels first described in the 17th century, is frequently associated with chylous effusion, respiratory failure, and high mortality in young patients, yet the underlying molecular pathogenesis and effective treatments remain elusive. Here, we identify an unexpected causal link between MAPK activation and defective development of the lymphatic basement membrane that drives lymphangiectasia. Human pathological tissue samples from patients diagnosed with lymphangiectasia revealed sustained MAPK activation within lymphatic endothelial cells. Endothelial KRASG12D–mediated sustained MAPK activation in newborn mice caused severe pulmonary and intercostal lymphangiectasia, accumulation of chyle in the pleural space, and complete lethality. Pathological activation of MAPK in murine vasculature inhibited the Nfatc1-dependent genetic program required for laminin interactions, collagen crosslinking, and anchoring fibril formation, driving defective development of the lymphatic basement membrane. Treatment with ravoxertinib, a pharmacological inhibitor of MAPK, reverses nuclear-to-cytoplasmic localization of Nfatc1, basement membrane development defects, lymphangiectasia, and chyle accumulation, ultimately improving survival of endothelial KRAS mutant neonatal mice. These results reveal defective lymphatic basement membrane assembly and composition as major causes of thoracic lymphangiectasia and provide a potential treatment.
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影响因子：
11.8
作者：
Bazigou, Eleni;Xie, Sherry;Chen, Chun;Weston, Anne;Miura, Naoyuki;Sorokin, Lydia;Adams, Ralf;Muro, Andres F.;Sheppard, Dean;Makinen, Taija
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Makinen, Taija
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作者：
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通讯作者：
Schwarz, Jacob B.
影响因子：
56.9
作者：
BARKER, DF;HOSTIKKA, SL;TRYGGVASON, K
通讯作者：
TRYGGVASON, K