Small-molecule-induced neuron-specific hypoxia: recapitulating developmental angiogenesis for ischemic stroke therapy

Hypoxia has therapeutic potential, but global hypoxia is toxic. Inducing safe, cell-specific hypoxia remains a clinically unmet need. We hypothesized that small-molecule-augmented oxygen consumption in adjacent cells induces neuron-specific hypoxia, representing a safe ischemic stroke strategy that mimics neural-directed developmental neovascularization. Using single-cell sequencing, a hypoxic probe, and knockout mice, we showed that ADT-OH (an active metabolite of a hepatoprotective drug) targeted sulfide-quinone oxidoreductase (SQR) to increase aerobic respiration in microglia/macrophages, thereby generating neuron-specific hypoxia after cerebral ischemia. Neuronal hypoxia promoted functional angiogenesis by specifically stabilizing hypoxia-inducible factor to upregulate the expression of neuron-derived vascular endothelial growth factor, supporting a neural-directed angiogenic mechanism. ADT-OH also restored the blood-brain barrier (BBB) via microglial/macrophage SQR. Notably, microglia/macrophage UCP2, the downstream mediator of SQR, was required for ADT-OH-induced BBB repair but not angiogenesis. Mechanistically, ADT-OH targeted UCP2 to increase Wnt/β-catenin signaling, which has been shown to mediate developmental BBB formation. In summary, one small molecule targeting SQR achieves therapeutic cell-specific hypoxia.