Targeting coupling of type H-like vessels and cell fate transition to delay soft tissue aging.

The aging process exhibits tissue-specific characteristics, yet its underlying mechanisms remain poorly understood. While it is widely accepted that a reduction in blood vessels in hard tissues contributes to aging, such as in osteoporosis, the vascular changes driving soft tissue aging and degeneration remain unclear. Here, by integrating single-cell transcriptomics and light-sheet imaging, we uncover a striking infiltration of type H-like blood vessels and an aging-specific Coch+ cell subpopulation in aging soft tissues. In a tamoxifen-inducible type H-like blood vessel proliferation mouse model, type H-like blood vessel expansion correlates with impaired locomotor function and accelerated senescence in soft tissues. Following infiltration, type H-like blood vessels secrete CXCL12, driving aberrant differentiation of stem/progenitor cells. Furthermore, Coch+ cell subpopulation promotes type H-like blood vessel invasion via ANG2/VEGF-A signaling. Notably, reducing type H-like blood vessels or inhibiting ANG2/VEGF-A in aging mice, we observed delayed soft tissue aging and improved locomotor function. These findings reveal an underlying mechanism linking vascular infiltration and pathological cell fate transitions in soft tissue aging, highlighting the therapeutic potential of targeting the coupling of type H-like blood vessels and cell fate transition to delay soft tissue aging.