STABILIZATION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR MESSENGER-RNA BY HYPOXIA AND HYPOGLYCEMIA AND COREGULATION WITH OTHER ISCHEMIA-INDUCED GENES

Expression of vascular endothelial growth factor (VEGF), an endothelia l cell-specific mitogen and a potent angiogenic factor, is upregulated in response to a hypoxic or hypoglycemic stress. Here we show that th e increase in steady-state levels of VEGF mRNA is partly due to transc riptional activation but mostly due to increase in mRNA stability, Bot h oxygen and glucose deficiencies result in extension of the VEGF mRNA half-life in a protein synthesis-dependent manner, Viewing VEGF as a stress-induced gene, we compared its mode of regulation with that of o ther stress-induced genes, Results showed that under nonstressed condi tions, VEGF shares with the glucose transporter GLUT-1 a relatively sh ort half-life (0.64 and 0.52 h, respectively), which is extended fourf old and more than eightfold, respectively, when cells are deprived of either oxygen or glucose. In contrast, the mRNAs of another hypoxia-in ducible and hypoglycemia-inducible gene, grp78, as well as that of HSP 70, were not stabilized by these metabolic insults, To show that VEGF and GLUT-1 are coinduced in differentially stressed microenvironments, multicell spheroids representing a clonal population of glioma cells in which each cell layer is differentially stressed were analyzed by i n situ hybridization, Cellular microenvironments conducive to inductio n of VEGF and GLUT-1 were completely coincidental, These findings show that two different consequences of tissue ischemia, namely, hypoxia a nd glucose deprivation, induce VEGF and GLUT-1 expression by similar m echanisms, These proteins function, in turn, to satisfy the tissue nee ds through expanding its vasculature and improving its glucose utiliza tion, respectively.