Data from: 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-vascular
ingrowth. This phenotype was HIF1α-dependent, since co-deleting HIF1α
rescued tendon morphology and mechanics. Moreover, deleting vascular
endothelial growth factor A (VEGFA) alongside VHL effectively suppressed
neovascularization, but failed to rescue extracellular matrix
abnormalities or restore mechanical function, emphasizing a direct role of
HIF1α in driving tendon disease independently of angiogenesis.
Mechanistically, we found that HIF1α activation was strain-dependent in
primary cultured human tendon cells and induced by mechanical overload in
murine tendon explants. Furthermore, genetically removing HIF1α from
tenocytes prevented aberrant tendon remodeling in response to chronic
overload. These findings position HIF1α signaling as a central driver of
tendinopathy that acts through a maladaptive tissue response to chronic
overload, providing mechanistic insights that could be leveraged for
improved therapeutic approaches.