Vascular ingrowth in intervertebral disc degeneration: Mechanistic insights, current progress, and therapeutic perspectives

Intervertebral disc degeneration (IDD), a primary cause of low back pain, currently lacks therapeutic strategies capable of halting its progression or promoting disc regeneration. Vascular ingrowth is the hallmark pathological feature of IDD, which arises from annulus fibrosus (AF) injury and accelerates degenerative processes through intricate interactions with inflammation and extracellular matrix degradation. This review summarizes the characteristics of vascular ingrowth in IDD, including differential vascular distribution between normal and degenerative discs, spatiotemporal dynamics of progressive invasion, and its association with pain via neurovascular co-invasion. The key underlying mechanisms involve the activation of pro-angiogenic factors (e.g., vascular endothelial growth factor [VEGF]), regulation by miRNA networks (e.g., miR-140-5p), macrophage-mediated coupling of inflammation and angiogenesis, and the dual roles of stress pathways and hypoxia-inducible factor signaling in driving pathological vascularization. Current research employs in vivo models (e.g., puncture- or fixation-induced degeneration), in vitro vascular co-culture systems, as well as advanced imaging techniques to dissect the process of vascular ingrowth in IDD. Aimed at counteracting pathological angiogenesis and halting the progression of IDD, emerging therapeutic strategies have been developed, including VEGF interventions, miRNA-targeted therapies, modulation of the inflammatory microenvironment, and multi-target combinatorial regimens. Despite substantial advances in understanding vascular ingrowth, several critical unresolved issues remain, including the unclear causal relationship between vascular ingrowth and IDD progression, species-specific disparities in preclinical models, and challenges in optimizing therapeutic timing and target selection. Future research will focus on addressing these gaps, with key priorities including single-cell analysis of vascular heterogeneity, mechanobiological coupling with vascularization, biomaterial-based precision regulation, and the establishment of standardized clinical translation pathways. In summary, vascular ingrowth is a critical driver of IDD, and mechanistic insights gained herein support its potential as a therapeutic target. Addressing current challenges will accelerate the translation of novel strategies into clinical practice for effective IDD management.