Microtubule detyrosination enhances matrix remodeling and force transmission during endothelial sprouting

Abstract Angiogenic sprouting relies on the coordinated regulation of endothelial migration, force generation, and extracellular matrix (ECM) remodeling. While microtubules are known to regulate cell polarity and migration, how tubulin post-translational modifications reshape microtubule behavior and impact matrix-dependent migration programs remain unclear. Here, using sprouting angiogenesis as an integrative physiological context, we combine live-cell imaging, three-dimensional (3D) sprouting and microfluidic invasion assays, and 3D traction force microscopy to dissect the role of tubulin detyrosination and acetylation. We show that microtubule detyrosination, in contrast to acetylation, promotes directional persistence, sprout elongation and collective endothelial invasion. Detyrosinated microtubules remain dynamic and display more persistent growth, supporting sustained directional migration. Strikingly, microtubule detyrosination also enhances ECM remodeling, leading to increased matrix degradation and augmented traction force transmission. Functional inhibition experiments reveal that matrix degradation, rather than actomyosin contractility, is required for both elevated forces and enhanced sprouting. Together, these findings identify microtubule detyrosination as a key regulator linking cytoskeletal dynamics, cell migration and matrix remodeling during angiogenesis.