Intermittent hypoxia protects against hypoxic-ischemic brain damage by inducing functional angiogenesis

Ischemic stroke (IS) induces neurological damage due to cerebrovascular occlusion. Restoring blood perfusion to the ischemic brain area in a timely fashion is the most effective treatment strategy. Hypoxia is an effective way of restoring blood perfusion by improving cerebrovascular microcirculation, while the effect varies greatly depending on hypoxic mode. This study aimed to screen for the optimal hypoxic mode to improve cerebrovascular microcirculation and prevent IS. Here, we found that compared with continuous hypoxia (CH), intermittent hypoxia (IH) significantly improved cerebral blood flow and oxygen saturation in mice without causing neurological impairment. By analyzing cerebrovascular microcirculation from mice, we found that the IH mode (13%, 5*10) with 13% O 2 , 5 min interval, and 10 cycles per day significantly improved the cerebrovascular microcirculation by promoting angiogenesis without affecting the integrity of the blood-brain barrier. In addition, IH (13%, 5*10) treatment of distal middle cerebral artery occlusion (dMCAO) mice significantly alleviated neurological dysfunction and reduced cerebral infarct volume by improving cerebrovascular microcirculation. CH had none of these positive effects. In summary, our study screened for an appropriate intermittent hypoxic mode that could improve cerebrovascular microcirculation, laying a theoretical foundation for the prevention and treatment of IS in clinical practice.