Tie2 Activation Enhances Vascularized Lymph Node Transfer in Lymphedema by Improving Lymphatic Endothelial Integrity.

Abstract

BACKGROUND: Lymphedema (LE) is characterized by inadequate interstitial fluid drainage because of disrupted lymphatic vasculature. Despite the pivotal role of angiopoietin (Ang)-Tie2 signaling in lymphatics, the therapeutic potential of Tie2 modulation in LE remains unknown. METHODS: This study investigates the molecular and pathologic changes associated with LE and transcriptomic analyses. In addition, a mouse hindlimb LE model was established by obstructing superficial and deep lymphatic drainage, allowing the evaluation of structural, functional, and molecular alterations accompanying LE. The effects of systemically administered Ang2-binding and Tie2-activating antibody (ABTAA) on LE were assessed, both independently and in combination with vascularized lymph node transfer (VLNT). RESULTS: Immunohistochemistry and transcriptomic analyses of tissues from LE patients revealed significant impairment of lymphatic endothelial cell (LEC) junctions and alterations in Ang-Tie2 signaling. A mouse hindlimb LE model demonstrated the hallmarks of LE, including fluid drainage impairment along with tissue edema, disintegrated LECs, and remodeling of lymphatic vessels. ABTAA significantly improved all the features of LE by activating lymphatic endothelial Tie2, leading to increased LEC junctional stability. Notably, ABTAA exerted an additive effect in relieving LE when combined with VLNT, which was supported by transcriptomic analysis results that indicated enhanced lymphatic vascular integrity, reduced inflammation, and increased vasculogenesis on treatment. CONCLUSIONS: Tie2 activation with ABTAA ameliorates LE 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 LE. 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 VLNT for LE.