Macrophage Dab1 Links Early Hypoxia to Adaptive Angiogenesis to Drive Peripheral Nerve Repair.

Effective nerve regeneration depends on the precise spatiotemporal coordination of immune responses and adaptive angiogenesis, often driven by injury-induced hypoxia. However, how early hypoxic signals are sensed and translated into vascular niches remains poorly understood. Using peripheral nerve injury as a model, we show that hypoxia exerts stage-specific functions dictating regenerative outcomes. Suppressing the early hypoxic response by premature oxygen supplementation lowers HIF-1α, attenuates angiogenesis, and ultimately compromises long-term regeneration, whereas prolonged hypoxia ex vivo causes axonal and myelin injury. Using spatiotemporal hypoxia mapping, genetic mouse models, and human nerve specimens, we identify Disabled-1 (Dab1) as a previously unrecognized hypoxia-responsive adaptor that is prominently induced in macrophages and links hypoxia to angiogenesis. Macrophage-specific Dab1 deletion diminishes HIF-1α/VEGF-A signaling, impairs vascular remodeling, and delays nerve regeneration, whereas enhancing Dab1 signaling improves the regenerative microenvironment. Mechanistically, Dab1 sustains hypoxia-associated HIF-1α accumulation, partially through the Na