Urbich Carmen, Stein Monika, Reisinger Kerstin, Kaufmann Roland, Dimmeler Stefanie, Gille Jens
Molecular Cardiology, Department of Internal Medicine IV, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
FEBS Lett. 2003 Jan 30;535(1-3):87-93. doi: 10.1016/s0014-5793(02)03879-6.
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.
血流动力学力在调节内皮细胞存活中起重要作用。由于先前已证明通过血管内皮生长因子（VEGF）受体-2途径的信号传导会影响内皮细胞存活，我们推测层流切应力可能部分通过诱导VEGF受体-2表达来促进细胞存活。本研究表明，在微血管和大血管来源的内皮细胞中，流体切应力可使内皮VEGF受体-2表达呈时间和剂量依赖性上调。对VEGF受体-2启动子5'-调控区的功能分析将切应力反应元件定位到bp -60至-37之间的序列，该序列包含两个相邻的共有Sp1转录因子结合位点。组成型和切应力诱导型Sp1依赖性复合物与该元件结合，表明流体切应力诱导的VEGF受体-2基因转录激活需要Sp1依赖性DNA结合。总之，这些结果表明生物力学刺激可能通过上调VEGF受体-2表达导致内皮细胞存活。
