Ventilation with high oxygen partial pressures, delivered during or after ischemia, has been shown to improve outcome from ischemia in rats. Animals which hibernate are adapted to hypoxia and are also more resistant to ischemia induced brain damage. These animals have increased oxygen levels in brain compared to controls. Exercise increases capillary density and is protective against ischemic damage. It is of major importance to determine if increased oxygen levels improve outcomes as the data on oxygen administration in patients is not conclusive. There is an additional potential mechanism of protection that relates to increased vascular density. Neural stem cells have been shown to be associated with the microvasculature. They also proliferate in a BKM120 mildly hypoxic environment. The weeks of hypoxia could stimulate proliferation and the increase in vascular density could result in a proportional increase in the concentration of neural stem cells. Long term intermittent hypoxic preconditioning resulted in less expression of the endothelial inflammatory markers of e-selectin reversible ischemia in rats. Some macrophage and microglial response after injury is necessary for scavenging the necrotic debris facilitating the plasticity. However, excess infiltration of leukocytes into the brain is detrimental and therapies that prevent the leukocyte infiltration during the acute phase after ischemia are neuroprotective. The reduced inflammatory response is additional evidence that the damage caused by ischemia was reduced in the acclimated group. One obvious question is whether people living at altitude have a higher incidence of stroke or a reduced severity. There is a limited body of work on incidence, but it would appear that the number of strokes actually increases at altitude for a given population. This has been reported for people living at altitude as well as for groups moving from a lowland to highland area. It is likely that this increased incidence relates in part to the increased hematocrit at altitude. Our data cannot be used to comment on incidence of stroke in high altitude populations. However we would predict that for a given vessel occlusion, the severity of infarction would be reduced in the group living at altitude. We could find no data relating to outcome. Could this neurological plasticity be harnessed to improve stroke tolerance in either the general population or in high risk patient groups? It has already been shown that short term exposure to pharmacological agents which increase HIF1-a may be neuroprotective. A broad spectrum of transcriptional changes occurs on exposure to hypoxia, many of which could provide some level of protection against hypoxic/ischemic damage in the brain if correctly stimulated. Such an intervention may be useful in high risk patients such as those who have had a transient ischemic attack. As stroke patients are often older, it will be important to understand the effect of aging on mechanisms of protection. The increase in HIF-1a observed in the brain with hypoxia exposure is reduced in the older animal. However, in studies on both rat and mouse brain, VEGF was significantly elevated in response to hypoxia, and the increase in capillary density was similar to that in the younger brain. These data indicate that the pathways regulating hypoxia response may differ in the aged brain, and the role of HIF-1a as a master switch may be reduced. This study shows that chronic hypoxia exposure provides significant protection against hypoxic/ischemic damage.