Activation of hypoxia inducible factor-1alpha in gastric mucosa in response to ethanol injury: a trigger for angiogenesis?

Gastric mucosal injury triggers angiogenesis and activation of VEGF expression, but the mechanism(s) of VEGF gene activation are not known. In some tissues (e.g. myocardium), hypoxia triggers activation of hypoxia-inducible factor-1alpha (HIF-1alpha), a transcription factor known to activate VEGF gene expression. This study was aimed to determine whether hypoxia and/or alcohol injury may induces HIF-1alpha in gastric mucosa. Normal rat gastric tissue was incubated in organ culture under either hypoxic or normoxic conditions for 6hrs. Rats received, intragastrically, either saline or alcohol and gastric mucosa bordering necrosis was obtained at 1-24hrs. HIF-1alpha mRNA and protein were determined by RT-PCR and Western-blot analysis. HIF-1alpha and VEGF proteins were localized by immunostaining. Incubation of normal gastric mucosa under hypoxia caused a significant elevation of HIF-1alpha mRNA (20+/-2%, p<0.05) and protein (262+/-15%, p<0.005) vs. normoxia. Following alcohol injury, gastric mucosa bordering necrosis demonstrated a significant increase in HIF-1alpha mRNA at 3 and 6hrs (40+/-4%, 19+/-2%; p<0.05), and protein (>300+/-16%; p<0.02 at all time points; highest at 1-3hrs). HIF-1alpha signal was detected in regenerating mucosal microvessels, where it co-localized with VEGF. Since HIF-1alpha initiates transcription of VEGF mRNA, HIF-1alpha activation by ethanol-induced injury is likely responsible for activation of VEGF gene and induction of angiogenesis.