LDL attenuates VEGF-induced angiogenesis via mechanisms involving VEGFR2 internalization and degradation following endosome-trans-Golgi network trafficking

被引:36
作者
Jin, Fengyan [1 ]
Hagemann, Nina [1 ]
Brockmeier, Ulf [2 ]
Schaefer, Simon T. [3 ]
Zechariah, Anil [1 ]
Hermann, Dirk M. [1 ]
机构
[1] Univ Hosp Essen, Dept Neurol, D-45122 Essen, Germany
[2] Univ Duisburg Essen, Dept Physiol, Essen, Germany
[3] Univ Hosp Essen, Dept Anaesthesiol & Intens Care Med, D-45122 Essen, Germany
关键词
Capillary formation; Endothelial cell; Vascular endothelial growth factor; ENDOTHELIAL GROWTH-FACTOR; LOW-DENSITY-LIPOPROTEIN; NITRIC-OXIDE SYNTHASE; PHASE-II; CELL PROLIFERATION; GENE-TRANSFER; DOUBLE-BLIND; HYPERCHOLESTEROLEMIA; ISCHEMIA; PATHWAY;
D O I
10.1007/s10456-013-9340-2
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
Considerable efforts have been made to amplify angiogenesis under conditions of hypoxia and ischemia by vascular endothelial growth factor (VEGF) delivery, so far with limited success. Ischemic vascular diseases are often associated with hypercholesterolemia. To elucidate whether the exposure to blood lipids influences VEGF responses of microvessels, we characterized effects of low density lipoprotein (LDL) exposure on the proliferation, migration and tube formation of human umbilical vein endothelial cells. By examining the expression, phosphorylation and downstream signals of VEGF's receptor VEGFR2, we characterized mechanisms controlling angiogenic responses following LDL exposure. LDL attenuated endothelial proliferation, migration and tube formation in a dose-dependent way. Reduced abundance of VEGFR2 and VEGFR1 were noticed in LDL-exposed endothelial cells. In subcellular localization studies that we combined with pharmacological experiments, we showed that the loss of VEGFR2 resulted from its internalization and degradation, the latter of which required syntaxin-16-dependent endosome-trans-Golgi network trafficking. As a consequence, VEGFR2 phosphorylation and downstream signals -specifically Akt and ERK1/2 phosphorylation- were attenuated in response to VEGF treatment. VEGF only partly reversed the effects of LDL on angiogenesis under conditions of normoxia and hypoxia. Our results suggest that angiogenic responses to VEGF are compromised in hypercholesterolemia as a consequence of endosomal VEGFR2 degradation.
引用
收藏
页码:625 / 637
页数:13
相关论文
共 42 条
[1]   ApoB-containing lipoproteins regulate angiogenesis by modulating expression of VEGF receptor 1 [J].
Avraham-Davidi, Inbal ;
Ely, Yona ;
Pham, Van N. ;
Castranova, Daniel ;
Grunspan, Moshe ;
Malkinson, Guy ;
Gibbs-Bar, Liron ;
Mayseless, Oded ;
Allmog, Gabriella ;
Lo, Brigid ;
Warren, Carmen M. ;
Chen, Tom T. ;
Ungos, Josette ;
Kidd, Kameha ;
Shaw, Kenna ;
Rogachev, Ilana ;
Wan, Wuzhou ;
Murphy, Philip M. ;
Farber, Steven A. ;
Carmel, Liran ;
Shelness, Gregory S. ;
Iruela-Arispe, M. Luisa ;
Weinstein, Brant M. ;
Yaniv, Karina .
NATURE MEDICINE, 2012, 18 (06) :967-+
[2]   Ligand-Stimulated VEGFR2 Signaling is Regulated by Co-Ordinated Trafficking and Proteolysis [J].
Bruns, Alexander F. ;
Herbert, Shane P. ;
Odell, Adam F. ;
Jopling, Helen M. ;
Hooper, Nigel M. ;
Zachary, Ian C. ;
Walker, John H. ;
Ponnambalam, Sreenivasan .
TRAFFIC, 2010, 11 (01) :161-174
[3]   Oxidized low-density lipoprotein downregulates endothelial basic fibroblast growth factor through a pertussis toxin-sensitive G-protein pathway - Mediator role of platelet-activating factor-like phospholipids [J].
Chang, PY ;
Luo, S ;
Jiang, T ;
Lee, YT ;
Lu, SC ;
Henry, PD ;
Chen, CH .
CIRCULATION, 2001, 104 (05) :588-593
[4]  
Chavakis E, 2001, CIRCULATION, V103, P2102
[5]   Oxidized low-density lipoproteins inhibit endothelial cell proliferation by suppressing basic fibroblast growth factor expression [J].
Chen, CH ;
Jiang, W ;
Via, DP ;
Luo, S ;
Li, TR ;
Lee, YT ;
Henry, PD .
CIRCULATION, 2000, 101 (02) :171-177
[6]   Activation of protease calpain by oxidized and glycated LDL increases the degradation of endothelial nitric oxide synthase [J].
Dong, Yunzhou ;
Wu, Yong ;
Wu, Mingyuan ;
Wang, Shuangxi ;
Zhang, Junhua ;
Xie, Zhonglin ;
Xu, Jian ;
Song, Ping ;
Wilson, Kenneth ;
Zhao, Zhengxing ;
Lyons, Timothy ;
Zou, Ming-Hui .
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, 2009, 13 (9A) :2899-2910
[7]  
Duan J, 2000, CIRCULATION, V102, P370
[8]   Increased Blood-Brain Barrier Permeability and Brain Edema After Focal Cerebral Ischemia Induced by Hyperlipidemia Role of Lipid Peroxidation and Calpain-1/2, Matrix Metalloproteinase-2/9, and RhoA Overactivation [J].
Elali, Ayman ;
Doeppner, Thorsten R. ;
Zechariah, Anil ;
Hermann, Dirk M. .
STROKE, 2011, 42 (11) :3238-U501
[9]   The biology of VEGF and its receptors [J].
Ferrara, N ;
Gerber, HP ;
LeCouter, J .
NATURE MEDICINE, 2003, 9 (06) :669-676
[10]   Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase Akt signal transduction pathway -: Requirement for Flk-1/KDR activation [J].
Gerber, HP ;
McMurtrey, A ;
Kowalski, J ;
Yan, MH ;
Keyt, BA ;
Dixit, V ;
Ferrara, N .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (46) :30336-30343