Microglia-vascular interactions after spinal cord injury: regulatory mechanisms and therapeutic advances

The repair process following spinal cord injury (SCI) involves intricate crosstalk between neuroimmune and vascular systems, with microglia-vascular interactions increasingly recognized as an important regulatory interface that may shape both secondary injury progression and neural regeneration. This review delineates the dual role of angiogenesis in SCI: functionally mature neovessels can facilitate restoration of blood supply, provide neurotrophic support, and offer guidance cues for axonal regrowth; in contrast, structurally abnormal and hyperpermeable vessels can exacerbate blood-spinal cord barrier (BSCB) disruption, amplify inflammatory responses, and perpetuate local hypoxia, thereby impeding functional recovery. As the primary resident immune cells of the central nervous system (CNS), microglia substantially influence the initiation, extension, and maturation of angiogenesis through dynamic, context-dependent functional states that are often operationally discussed within the M1/M2 framework. Conversely, vascular injury, barrier leakage, hypoxia-associated signaling, and endothelial-derived mediators can reshape microglial activation and function, establishing a bidirectional interaction network. Therapeutic strategies targeting this axis are shifting from indiscriminate angiogenesis promotion toward multimodal and stage-aware interventions, including modulation of microglial states, exosome-mediated delivery of bioactive molecules, functionalized biomaterial scaffolds, pathway-directed pharmacological approaches, and integration of physical rehabilitation strategies. These approaches have shown encouraging effects in preclinical models, including improved vascular maturation, reduced inflammatory injury, and better neurological outcomes. Future studies should combine single-cell multi-omics, spatially resolved profiling, in vivo imaging, and smart biomaterials to clarify the spatiotemporal dynamics of distinct cellular subpopulations, strengthen the preclinical evidence base, and support more rigorous translation of microglia-vascular axis regulation for SCI repair.