HIF1α gates tendon response to overload and drives tendinopathy independently from vascular recruitment

To investigate the role for HIF1α stabilization in tendon pathology, we generated mice with a tendon cell-targeted knockout of von Hippel-Lindau (VHL) protein by intercrossing ScxCre mice, in which Cre recombinase is under the Scleraxis promoter, with mice carrying the loxP -flanked Vhl alleles. VHL acts as a ubiquitin ligase that marks HIFs for proteolytic degradation under normoxic conditions, thereby silencing the HIF dependent transcriptional program. Hence, Vhl knockout results in stabilization of HIFs. We then performed gene expression analysis of tail tendon fascicles to confirm the activation of a HIF-dependent angiogenic and metabolic transcriptional program in the knockout mice compared to the wild types.