Tie2 activation enhances vascularized lymph node transfer in lymphedema by improving lymphatic endothelial integrity

Background: Lymphedema is characterized by inadequate interstitial fluid drainage due to disrupted lymphatic vasculature. Despite the pivotal role of angiopoietin (Ang)-Tie2 signaling in lymphatics, the therapeutic potential of Tie2 modulation in lymphedema remains unknown. Methods: To investigate the molecular and pathological changes associated with lymphedema, fat tissues were collected from lymphedema patients and subjected to immunohistochemistry and transcriptomic analyses. Additionally, a mouse hindlimb lymphedema model was established by obstructing superficial and deep lymphatic drainage, allowing the evaluation of structural, functional, and molecular alterations accompanying lymphedema. The effects of systemically administered Ang2-binding and Tie2-activating antibody (ABTAA) on lymphedema were assessed, both independently and in combination with vascularized lymph node transfer (VLNT). Results: Immunohistochemistry and transcriptomic analyses of tissues from lymphedema patients revealed significant impairment of lymphatic endothelial cell (LEC) junctions and alterations in Ang-Tie2 signaling. A mouse hindlimb lymphedema model demonstrated the hallmarks of lymphedema, including fluid drainage impairment along with tissue edema, disintegrated LECs, and remodeling of lymphatic vessels. ABTAA significantly improved all the features of lymphedema by activating lymphatic endothelial Tie2, leading to increased LEC junctional stability. Notably, ABTAA exerted an additive effect in relieving lymphedema when combined with VLNT, which was supported by transcriptomic analysis results that indicated enhanced lymphatic vascular integrity, reduced inflammation, and increased vasculogenesis upon treatment. Conclusions: Tie2 activation with ABTAA ameliorates lymphedema in a mouse model, both independently and in combination with VLNT treatment. These findings suggest that Tie2 activation may present a novel and effective option, potentially improving the current treatment of lymphedema. Clinical Relevance Statement: The results of the study highlight the potential of ABTAA treatment in enhancing lymphatic stability, offering plastic surgeons a novel therapeutic approach to improving outcomes in patients undergoing vascularized lymph node transfer for lymphedema. Graphical Abstract: A graphical abstract is available for this article.