UC San Diego

Hypoxia-inducible transcription factors (HIF) mediate the transcription of a wide range of physiologically important genes including erythropoietin (EPO) and vascular endothelial growth factor (VEGF) to maintain oxygen homeostasis during development, (patho)-physiological adaptation, and ischemia. Previous studies have elucidated the molecular mechanisms underlying HIF activity with EPO and VEGF induction, but little has been done to understand the affects of these hypoxia-inducible genes with the physiology of blood flow in vivo. In an attempt to explain this, two complementary measures, vascular lumen diameter and red blood cell velocity, are used to characterize the vascular dynamics of individual capillaries in mice with conditional deletions in astrocytes of the major factors that mediate hypoxic transcriptional response and regulate EPO and VEGF, i.e., HIF-1\[alpha\], HIF-2\[alpha\] and their negative regulator VHL. In this thesis I show that vascular dynamics are altered primarily through a HIF- 2\[alpha\]dependent pathway with respect to cerebral blood flow.