Disruption of YAP biomolecular condensates by mechanical stress drives intervertebral disc vascularization

Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine

Angiogenesis represents a key pathological basis for intervertebral disc degeneration (IDD) and discogenic low back pain (LBP), yet its underlying mechanisms remain elusive. Here, we show that mechanical stress induces disc vascularization by activating Hippo signaling and inducing Yes-associated protein (YAP) degradation in nucleus pulposus (NP) cells. This finding was corroborated in NP-specificconditional knockout mice, which exhibited enhanced disc vascularization. Mechanistically, YAP undergoes liquid-liquid phase separation to form biomolecular condensates that recruit and sequester the transcription factor SNAI1. Disruption of the YAP condensates or release of SNAI1 restores SNAI1-mediated transcription, leading to the up-regulation of its target proangiogenic factors ANGPTL4 and VEGFA, which synergistically promote intervertebral disc angiogenesis through metabolic support and signaling activation. Last, using a microneedle delivery system loaded with NP cell membrane–coated liposomes, we demonstrated that targeted inhibition of the Hippo pathway or SNAI1 in NP effectively alleviates mechanical stress–induced disc vascularization, suggesting an effective strategy for alleviating LBP. YAP suppresses disc angiogenesis through phase separation–mediated SNAI1 sequestration. teaser