Neuropediatrics 2005; 36 - P4
DOI: 10.1055/s-2005-867989

Hypoxia-inducible factor 1 (HIF-1)-regulated vasoactive factors in rat brain: gene expression in relation to the degree of global hypoxia in vivo

S Bani Hashemi 1, J Dötsch 1, W Rascher 1, D Wenzel 1, R Trollmann 1
  • 1Klinik für Kinder und Jugendliche der Universität, Erlangen

Objectives: The transcription factor HIF-1 is known as an important adaptation mechanism of immature and adult brain to hypoxia/ischemia and reoxygenation/reperfusion failure. HIF-1α modulates the expression of metabolic, vasoactive and anti-apoptotic factors (e.g. EPO; glycolytic enzymes; vascular endothelial growth factor, VEGF; inducible NO synthase, iNOS) in selectively vulnerable CNS regions. Promising neuroprotective effects have been shown. We investigated effects of systemic hypoxia of different duration on the mRNA expression of HIF-1α, iNOS and VEGF in rat CNS.

Material and Methods: Rat CNS (Sprague-Dawley, juvenile) was investigated after incubation (duration: 3 and 12h) of the animals under hypoxia (8% O2, n=5), CoCl2 (60mg/kg s.c., n=4), which functions as a chemical stabilizer of the HIF-1α protein, or normoxia (n=5). Messenger RNA levels for HIF-1α, VEGF and iNOS were measured by quantitative PCR (TaqMan real-time PCR; housekeeping genes: porphobilinogen deaminase, PBGD; hypoxanthine-guanine phosphoribosyltransferase, HPRT).

Results: (mean±SEM): HIF-1α/PBGD mRNA levels were similar in hypoxic and normoxic tissues. Hypoxia significantly increased VEGF/PBGD mRNA levels within 3h (1.89±0.32; p<0.01) and 12h of incubation (3.37±0.92; <0.01) compared to controls (3h: 0.39±0.12; 12h: 0.69±0.20). There was no significant up-regulation of VEGF/PBGD mRNA in response to CoCl2. Inducible NOS/PBGD mRNA levels significantly increased after 12h of hypoxia (1.16±0.91, p<0.01) and CoCl2 injection (1.11±1.07) but not after 3h of hypoxia (0.29±0.11) compared to normoxia (0.20±0.08).

Conclusions: We found a different dynamic of the induction of iNOS and VEGF in rat brain in relation to the duration of hypoxic stimulus. Our data indicate that VEGF is up-regulated not only in chronic hypoxia/ischemia but also in the early adaptation period to isolated acute cerebral hypoxia.