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

Tendons are sparsely vascularized connective tissues that link muscles to bones, withstanding some of the highest mechanical stresses in the body. Mechanical overloading and tissue hypervascularity are implicated in tendinopathy, a common musculoskeletal disorder, yet their mechanistic roles remain unclear. Here, we identify HIF1α not only as a marker but as a driver of tendinopathy. Initial histological and multi-omics evaluation of human tendinopathic samples revealed extensive extracellular matrix remodeling, including pathological collagen crosslinking coinciding with active hypoxic signaling. Hypothesizing a causal contribution of hypoxia signaling, we generated mice with tenocyte-targeted deletions of the Von Hippel-Lindau (VHL) gene, which controls hypoxia signaling by regulating HIFα degradation. We demonstrated that VHL inactivation suffices to induce pathological hallmarks of tendinopathy, such as collagen matrix disorganization, crosslinking, altered mechanics, and neuro-vasc..., , , # Data from: HIF1α gates tendon response to overload and drives tendinopathy independently of vascular recruitment

Dataset DOI: [10.5061/dryad.x3ffbg80h](https://doi.org/10.5061/dryad.x3ffbg80h)

## Description of the data and file structure

Bulk RNA sequencing of two separate datasets was performed to investigate transcriptional responses of human long head of the biceps tendon (LHBT) tissue and tendon-derived cells under different mechanical loading conditions. The first dataset (*Kallisto_LHBT_Prox_Dist*) includes RNA-seq data from frozen proximal and distal LHBT tissue samples collected during shoulder surgery. These samples were examined by a pathologist, histopathologically scored, and characterized for matrix composition and collagen crosslink content. The second dataset (*Kallisto_TendonSheets*) comprises RNA-seq data from primary human tendon-derived cells cultured in silicone chambers. After three days of culture with ascorbic acid supplementation, the cells were subjected t...