Proteomic profiling of tendon-specific VHL knockout and VHL-dependent double knockout mouse tail tendon fascicles

This study investigates how chronic activation of HIF1α in tendon cells drives pathological extracellular matrix (ECM) remodeling and whether these changes can be modulated by genetic rescue strategies. Using tendon cell-specific deletion of Vhl (Scx;Vhl) in mice, which stabilizes HIF1α, we observed proteomic signatures consistent with maladaptive matrix remodeling, including upregulation of wound-associated proteins and loss of structural collagens. To disentangle the contribution of HIF1α from HIF2α, we generated double knockout mice lacking both Vhl and Hif1a in tendon cells (Scx;Vhl;Hif1α), which normalized many of the ECM changes and mechanical defects, demonstrating a central role of HIF1α. In parallel, to test whether vascular infiltration contributes to matrix pathology, we crossed Scx;Vhl mice with Vegfa floxed mice (Scx;Vhl;Vegfa). While VEGFA deletion prevented neovascularization and reduced innervation, ECM proteomics and mechanical properties largely remained pathological, indicating that HIF1α-dependent ECM remodeling occurs independently of vascular ingrowth. Together, this dataset provides a comprehensive proteomic characterization of tendon ECM changes induced by HIF1α stabilization and clarifies the distinct roles of HIF1α and VEGFA-driven angiogenesis in tendon disease.