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.
Ndubuizu
Obinna I
OI
Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue BRB 501A, Cleveland, OH 44106-4930, USA. oin@case.edu
Tsipis
Constantinos P
CP
Li
Ang
A
LaManna
Joseph C
JC
D000367:Age Factors; D000375:Aging; D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D000860:Hypoxia / Q000473:pathology* / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C495679:Slc2a1 protein, rat; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A