Oxygen Sensing, Hypoxia Inducible Factor 1 (HIF-1) Expression, and Hypoxia-Induced Angiogenesis in the Aged Rat Brain
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HIF-1 is a heterodimeric transcription factor with a regulatory α subunit and a constitutive β subunit. HIF-1 regulates the expression of a vast number of target genes which play role in adaptive physiological processes including: increase in oxygen delivery, angiogenesis, migration/motility, proliferation/apoptosis, vasomotor regulation, energy metabolism, pH regulation, and iron metabolism. The regulation of HIF-1 primarily depends on a family of 2-oxoglutarate and iron (II)-dependent oxygen sensors, the prolyl hydroxylases (PHDs). These enzymes catalyze the oxygen-dependent posttranslational modification of the HIF-1α subunit, regulating its stability as well as the HIF-1 transcriptional activity.
This dissertation work demonstrates a defect of this key oxygen-sensing and hypoxic-response mechanism in the aged cortex with the hypoxic-induced HIF-1α response and HIF-1 transcriptional activation being completely attenuated. This attenuation directly correlated with increased expression of the regulatory PHD enzymes (PHD 1 and 3) and had no effect on mRNA upregulation of HIF-independent genes. The posttranslational regulation (degradation) of HIF-2α under normoxic conditions is also attenuated in the aged cortex, suggesting differential regulation of HIF-1α and HIF-2α. The increased HIF-2α expression does not appear to induce target gene activation under acute hypoxic conditions in the aged cortex. The attenuated HIF-1α response remains during chronic hypoxic exposure. Despite this lack of HIF-1 activation, there is no significant difference in baseline or post-hypoxic brain capillary density counts between the young and old age groups. VEGF mRNA and protein levels are significantly elevated in the aged cortex during chronic hypoxic exposure despite the lack of HIF-1 activation. PPAR-γ coactivator (PGC)-1α, a known supplementary regulator of VEGF gene transcription, is elevated in the young and aged cortex during the chronic hypoxic exposure. These results suggest a compensatory HIF-1 independent preservation of hypoxic-induced microvascular angiogenesis in the aged rat brain.
Document number: case1307746474
Permalink: http://rave.ohiolink.edu/etdc/view?acc_num=case1307746474
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