HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Egr-1 gene is induced by the systemic administration of the vascular endothelial growth factor and the epidermal growth factor

Egr-1 is a transcription factor that couples short-term changes in the extracellular milieu to long-term changes in gene expression. In cultured endothelial cells, the Egr-1 gene has been shown to respond to a variety of extracellular signals. However, the physiological relevance of these findings remains unclear. To address this question, the growth factor-mediated response of the Egr-1 gene under in vivo conditions was analyzed. To that end, either vascular endothelial growth factor (VEGF) or epidermal growth factor (EGF) was injected into the intraperitoneal cavity of mice. Growth factors were delivered to all tissues examined, as evidenced by the widespread distribution of I125-labeled growth factors and the phosphorylation of their respective receptors. In Western blot analyses of whole-tissue extracts, Egr-1 protein levels were shown to be induced in the heart, brain, liver, and spleen of VEGF-treated mice, and in the heart, lung, brain, liver and skeletal muscle of EGFtreated animals. Changes in Egr-1 levels did not correlate with changes in receptor phosphorylation or ERK1/2 phosphorylation. In Northern blot analyses, VEGF induced Egr-1 mRNA levels in all tissues examined except lung and kidney, whereas EGF led to increased transcripts in all tissues except kidney. In immunofluorescence studies, VEGF induced Egr-1 in microvascular endothelial cells of the heart and liver, and EGF induced Egr-1 in the microvascular bed of skeletal muscle. Taken together, these results suggest that the Egr-1 gene is differentially regulated in response to systemically administered VEGF and EGF. (Blood. 2000; 96:1772-1781)