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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:907.)
© 2002 American Heart Association, Inc.

Vascular Biology

Shear Stress Induces Expression of Vascular Endothelial Growth Factor Receptor Flk-1/KDR Through the CT-Rich Sp1 Binding Site

Takeo Abumiya; Toshiyuki Sasaguri; Yoji Taba; Yoshikazu Miwa; Megumi Miyagi

From National Cardiovascular Center Research Institute, Osaka, Japan.

Correspondence to Takeo Abumiya, MD, PhD, Department of Neurosurgery, Keiwakai Ebetsu Hospital, 81-6 Nopporo Yoyogi, Ebetsu, Hokkaido 069-0817, Japan. E-mail abumiya{at}mbh.nifty.com

Abstract— Fluid shear stress is 1 of the major factors that control gene expression in vascular endothelial cells. We investigated the role of shear stress in the regulation of the expression of fetal liver kinase-1/kinase domain region (Flk-1/KDR), a vascular endothelial growth factor receptor, by using human umbilical vein endothelial cells. Laminar shear stress (15 dyne/cm²) elevated Flk-1/KDR mRNA levels by 3-fold for 8 hours, and the expression was upregulated within the range of 5 to 40 dyne/cm². Deletion analysis of the 5'-flanking region of the Flk-1/KDR gene promoter by use of a luciferase reporter vector revealed that a shear stress–responsive element resided in the sequence between -94 and -31 bp, which contained putative nuclear factor-B, activator protein-2, and GC-rich Sp1 and CT-rich Sp1 binding sites. Electrophoretic mobility shift assay demonstrated that nuclear extract was bound to the GC-rich Sp1 sites and the CT-rich Sp1 site with a similar pattern. However, shear stress enhanced the DNA-protein interactions only on the CT-rich Sp1 site but not on the GC-rich Sp1 sites. A 3-bp mutation in the CT-rich Sp1 site eliminated the response to shear stress in electrophoretic mobility shift assay and luciferase reporter assay. These results suggest that shear stress induces Flk-1/KDR expression through the CT-rich Sp1 binding site.

Key Words: shear stress • endothelial cells • transcription factors • gene expression

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