Abstracts
2000 Digestive Disease Week

# 2328 Reduced Expression of VEGF and Its Receptors in Portal Hypertensive Gastric Mucosa Following Alcohol Injury - a Key to Impaired Angiogenesis?
H. Kawanaka, M. Tomikawa, M. K. Jones, R. Pai, I. L. Szabo, K. Sugimachi, A. S. Tarnawski, I. James Sarfeh, Fukuoka, Japan, Irvine, CA, Long Beach, CA

Our previous study showed over 10-fold reduction of angiogenesis in portal hypertensive (PHT) gastric mucosa following ethanol (ETOH) injury (Gastroenterology 1994;106:702-708). To delineate the mechanisms, we studied expression of VEGF (endothelial specific angiogenic factor) and its receptors (Flk-1 and Flt-1) in gastric mucosa of PHT and sham-operated (SO) rats at baseline and after ETOH injury. METHODS: PHT was produced in 24 rats by staged portal vein ligation and 24 SO rats served as controls. After 14 days, rats received i.g. 50% ETOH. STUDIES at 3, 6 and 24 h after ETOH: (1) VEGF mRNA expression by RT/PCR and protein by Western blot analysis. (2) mRNA expression and phosphorylation of Flk-1 and Flt-1. RESULTS: (1) Expression of VEGF, Flk-1 and Flt-1 mRNAs were similar in both groups at the baseline. ETOH injury significantly increased VEGF mRNA expression (by 34 & 48%) and protein (by 111 & 89%) in SO rats at 3 and 6 h, respectively (p < 0.01 vs baseline); however, in PHT gastric mucosa , both VEGF mRNA and protein were significantly reduced by 25 & 37% and 32 & 25% at 3 and 6 h, respectively (p < 0.05 vs SO). (2) In SO rats, Flk-1 mRNA 6 h after ETOH injury was significantly increased by 169% (p < 0.01 vs baseline), while in PHT rats, it was significantly decreased. In SO rats, Flt-1 mRNA 3 h after ETOH injury was significantly increased by 165% (p < 0.01 vs baseline), but in PHT rats it was significantly decreased. Flk-1 and Flt-1 phosphorylation levels in SO rats following ETOH injury were significantly increased by 537 % and 330% at 24 h, respectively (p < 0.01 vs baseline), but in PHT rats, they remained unchanged. CONCLUSIONS: (1) In PHT gastric mucosa, increases in mRNAs of VEGF and its receptors, and phosphorylation of Flk-1 and Flt-1, in response to ETOH injury are significantly reduced vs SO. (2) Since VEGF and its receptors are essential for initiation of angiogenesis, these abnormalities can explain, at least in part, impaired angiogenesis in PHT gastric mucosa.