VEGF differentially activates STAT3 in microvascular endothelial cells.
Increased VEGF expression is found in several pathologies characterized by abnormal angiogenesis. Previous studies have shown that the transcription factor STAT3 mediates VEGF gene transcription and its activation. In this study, Western analysis and confocal immunocytochemistry were used to examine STAT3 activation in retinal microvascular endothelial cells (BREC). We found that VEGF rapidly induces STAT3 tyrosine phosphorylation and nuclear translocation. Immunoprecipitation studies also showed that VEGF forms a complex with VEGFR2 only in BREC and not in aortic macrovascular endothelial cells (BAEC). In addition, quantitative real-time RT-PCR analysis of VEGF-induced VEGF expression showed a significant increase in specific mRNA formation only in BREC and not in BAEC, and this effect was significantly reduced by antisense-mediated reduction of STAT3 expression. Furthermore, studies conducted in human dermal microvascular endothelial cells (HDMEC) showed that, in this endothelial cell type, VEGF autocrine expression is also accompanied by STAT3 activation as in BREC. In this study we showed that VEGF can differentially induce STAT3 activation in micro- versus macro-vascular endothelial cells and that this effect is linked to VEGFR2/STAT3 complex formation, which correlates with VEGF autocrine ability to stimulate its own gene expression.
Bartoli
Manuela
M
Vascular Biology Center, CB 3209, Medical College of Georgia, 1459 Laney Walker Blvd., Augusta, GA 30912, USA. mbartoli@mail.mcg.edu
Platt
Dan
D
Lemtalsi
Tahira
T
Gu
Xiaolin
X
Brooks
Steven E
SE
Marrero
Mario B
MB
Caldwell
Ruth B
RB
D021581:Active Transport, Cell Nucleus; D019898:Autocrine Communication; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D008833:Microcirculation / Q000378:metabolism; D008954:Models, Biological; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors
D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D040301:Vascular Endothelial Growth Factor Receptor-2