Up until recently, the prevailing view was that the structure of the mammalian brain was set during development and remained unchanged thereafter. Fifty years ago there were discussions and arguments on the existence of synaptic plasticity in brain and spinal cord that eventually established that at least the neurons could undergo continued structural rearrangements. Now it appears that there is much more plasticity in the CNS than previously conceived, extending to the vascular tree down to the level of the capillaries. With the introduction of the concept of the neurovascular unit it became clear that neurons, glia, and endothelial cells are capable of active reorganization throughout adult life. This plasticity has significant implications for brain function and pathophysiology. Apparently, capillary density is coupled to oxygen sufficiency. Consistently increased neuronal activity, for example during motor training exercises, leads to increased capillary density. Chronic hypoxic exposure, such as occurs, for example, during sojourns at altitude also lead to increased capillary density. Important components of the capillary plasticity regulation mechanism are the HIF-1 and HIF-2 transcription factors that regulate vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) acting through prostaglandin E and angiopoietin-2 (ang-2). With age, the HIF-1 signaling pathway becomes attenuated due to increased prolyl hydoxylase activity probably as a result of increased reactive oxygen species, which changes the set point for tissue oxygen detection. Thus, plasticity becomes increasingly impaired with aging making learning more difficult and increasing the brain vulnerability to cerebrovascular challenges. The increased cerebrovascular vulnerability with age suggests a potential strategy for treating cerebrovascular diseases like stroke and dementia. The strategy involves agents that restore or augment HIF-1 function. Augmentation of HIF-1 may be the prime mechanism for preconditioning and neuroprotection. One such strategy is through a ketogenic diet that leads to HIF-1 accumulation due to inhibition of prolyl hydroxylase. Discovery of angioplasticity has opened up new areas for research that elucidates brain function, provides new explanations for the neuropathology following cerebrovascular injury and dementia, and suggests potential new therapeutic approaches to prevent or resolve these insults.
Dioxide Dementia Ketone Prostaglandin Succinate
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This work was supported by grants from the USA National Institutes of Health NS38632, HL092933 and NS062048.
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