Hypoxia-inducible factor-1 (HIF-1)-independent microvascular angiogenesis in the aged rat brain

Angiogenesis is a critical component of mammalian brain adaptation to prolonged hypoxia. Hypoxia-induced angiogenesis is mediated by hypoxia-inducible factor-1 (HIF-1)-dependent transcriptional activation of growth factors, such as vascular endothelial growth factor (VEGF). Microvascular angiogenesis occurs over a 3-week period in the rodent brain. We have recently reported that HIF-1α accumulation and transcriptional activation of HIF target genes in the aged cortex of 24-month-old F344 rats is significantly attenuated during acute hypoxic exposure. In the present study, we show that cortical HIF-1α accumulation and HIF-1 activation remain absent during chronic hypoxic exposure in the aged rat brain (24-month-old F344). Despite this lack of HIF-1 activation, there is no significant difference in baseline or post-hypoxic brain capillary density counts between the young (3-month-old F344) and old age groups. VEGF mRNA and protein levels are significantly elevated in the aged cortex despite the lack of HIF-1 activation. Other HIF-independent mediators of hypoxia-inducible genes could be involved during chronic hypoxia in the aged brain. PPAR-γ coactivator (PGC)-1α, a known regulator of VEGF gene transcription, is elevated in the young and aged cortex during the chronic hypoxic exposure. Overall, our results suggest a compensatory HIF-1-independent preservation of hypoxic-induced microvascular angiogenesis in the aged rat brain.

Research highlights
► HIF-1α expression in the aged rat cortex remains attenuated during chronic hypoxia.
► No difference in baseline brain capillary density between young and aged rats.
► No difference in post-hypoxic brain capillary density between young and aged rats.
► HIF-1-independent increase in VEGF mRNA in the aged cortex during chronic hypoxia.
► Increased PGC-1α expression in the young and aged cortex during chronic hypoxia.