Fluid shear stress-induced transcriptional activation of the vascular endothelial growth factor receptor-2 gene requires Sp1-dependent DNA binding.
Hemodynamic forces play a fundamental role in the regulation of endothelial cell survival. As signaling via the vascular endothelial growth factor (VEGF) receptor-2 pathway has been previously demonstrated to impact endothelial cell survival, we hypothesized that laminar shear stress may facilitate survival in part by inducing VEGF receptor-2 expression. This study shows a time- and dose-dependent upregulation of endothelial VEGF receptor-2 expression by fluid shear stress in microvascular and large-vessel derived endothelial cells. A functional analysis of the 5'-regulatory region of the VEGF receptor-2 promoter localized the shear stress-response element to a sequence between bp -60 and -37 that encompasses two adjacent consensus Sp1 transcription factor binding sites. Constitutive and shear stress-inducible Sp1-dependent complexes are bound to this element, indicating that fluid shear stress-induced transcriptional activation of the VEGF receptor-2 gene requires Sp1-dependent DNA binding. Together, these results suggest that biomechanical stimulation may lead to endothelial cell survival by upregulating VEGF receptor-2 expression.
Urbich
Carmen
C
Molecular Cardiology, Department of Internal Medicine IV, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
Stein
Monika
M
Reisinger
Kerstin
K
Kaufmann
Roland
R
Dimmeler
Stefanie
S
Gille
Jens
J
D001665:Binding Sites; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D012333:RNA, Messenger / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000502:physiology; D020218:Response Elements / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D013314:Stress, Mechanical; D015533:Transcriptional Activation / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics* / Q000378:metabolism
D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D004247:DNA; D040301:Vascular Endothelial Growth Factor Receptor-2