Pathological MAPK activation-mediated lymphatic basement membrane disruption causes lymphangiectasia that is treatable with ravoxertinib
UMass Chan AffiliationsLi Weibo Institute for Rare Diseases Research
Molecular, Cell and Cancer Biology
Document TypeJournal Article
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AbstractLymphangiectasia, 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.
SourceJanardhan HP, Dresser K, Hutchinson L, Trivedi CM. Pathological MAPK activation-mediated lymphatic basement membrane disruption causes lymphangiectasia that is treatable with ravoxertinib. JCI Insight. 2022 Sep 8;7(17):e153033. doi: 10.1172/jci.insight.153033. PMID: 36073544; PMCID: PMC9536262.
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/53022
RightsCopyright: © 2022, Janardhan et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.; Attribution 4.0 International
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Except where otherwise noted, this item's license is described as Copyright: © 2022, Janardhan et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.