Cerebral Angioplasticity: The Anatomical Contribution to Ensuring Appropriate Oxygen Transport to Brain.

Abstract

In order to maintain proper function, mammalian brain requires a significant fraction of the energy provided through whole body oxygen consumption and oxidative phosphorylation. This has been fairly well known for a long time. More recently there has been an increased appreciation that, while whole brain blood flow remains fairly constant, there are large regional changes in local blood flow to account for spatial and temporal heterogeneity of neuronal activity. This latter phenomenon requires an extensive regulatory system for local oxygen delivery that involves arteriolar and capillary control mechanisms. The ISOTT has been a major contributor to the study of oxygen supply and demand through studies of the mechanisms of vascular dilation and constriction in response to energy expenditure and availability of substrate and oxygen. Nevertheless, it has become clear in the past few decades that in addition to acute, physiological responses to energy demand and oxygen/substrate availability, there are regulatory mechanisms that are continuously operating to control the capillary distribution over a time course of weeks. This process of "angioplasticity" results in the gradual acclimatization of the brain capillary bed to prolonged changes in oxygen/substrate availability and/or neuronal activity patterns. Angioplasticity is primarily regulated through the hypoxia inducible transcription factor, acting as a detector of the balance between oxygen delivery and energy demand at the level of the cell redox state, controlling vascular endothelial growth factor production which helps determine capillary density in consort with the cyclooxygenase-2/angiopoietin-2 pathway that controls endothelial cell junction mechanical stability. We can conclude that the structure-function of brain capillaries is regulated during prolonged challenges to energy supply-demand balance within the physiological range. We can conclude that over the physiological range of ambient oxygen, brain capillary density is proportional to fraction inspired oxygen. The primary mechanisms for regulation of brain capillary density are HIF-1/VEGF and COX-2/PGE2/ang-2 pathways of angiogenesis and angiolysis.