Angiomotin regulates endothelial cell migration during embryonic angiogenesis

被引:117
作者
Aase, Karin
Ernkvist, Mira
Ebarasi, Lwaki
Jakobsson, Lars
Majumdar, Arindam
Yi, Chunling
Birot, Olivier
Ming, Yue
Kvanta, Anders
Edholm, Dan
Aspenstrom, Pontus
Kissil, Joseph
Claesson-Welsh, Lena
Shimono, Akihiko
Holmgren, Lars [1 ]
机构
[1] Karolinska Inst, Canc Ctr Karolinska, Dept Oncol Pathol, SE-17176 Stockholm, Sweden
[2] Karolinska Inst, Dept Med Biochem & Biophys, Div Matrix Biol, SE-17177 Stockholm, Sweden
[3] Uppsala Univ, Rudbeck Lab, Dept Genet & Pathol, SE-75185 Uppsala, Sweden
[4] Wistar Inst Anat & Biol, Mol & Cellular Oncogenesis Program, Philadelphia, PA 19104 USA
[5] St Eriks Hosp, Karolinska Inst, Sect Ophthalmol & Vis, Dept Clin Neurosci, SE-11284 Stockholm, Sweden
[6] Ludwig Inst Canc Res, Biomed Ctr, SE-75124 Uppsala, Sweden
[7] RIKEN, Ctr Dev Biol, Chuou Ku, Kobe, Hyogo 6500047, Japan
关键词
angiostatin; neovascularization; embryogenesis; GTPase; chemotaxis; transgenic; zebrafish;
D O I
10.1101/gad.432007
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The development of the embryonic vascular system into a highly ordered network requires precise control over the migration and branching of endothelial cells (ECs). We have previously identified angiomotin (Amot) as a receptor for the angiogenesis inhibitor angiostatin. Furthermore, DNA vaccination targeting Amot inhibits angiogenesis and tumor growth. However, little is known regarding the role of Amot in physiological angiogenesis. We therefore investigated the role of Amot in embryonicneovascularization during zebrafish and mouse embryogenesis. Here we report that knockdown of Amot in zebrafish reduced the number of filopodia of endothelial tip cells and severely impaired the migration of intersegmental vessels. We further show that 75% of Amot knockout mice die between embryonic day 11 (E11) and E11.5 and exhibit severe vascular insufficiency in the intersomitic region as well as dilated vessels in the brain. Furthermore, using ECs differentiated from embryonic stem (ES) cells, we demonstrate that Amot-deficient cells have intact response to vascular endothelial growth factor (VEGF) in regard to differentiation and proliferation. However, the chemotactic response to VEGF was abolished in Amot-deficient cells. We provide evidence that Amot is important for endothelial polarization during migration and that Amot controls Rac1 activity in endothelial and epithelial cells. Our data demonstrate a critical role for Amot during vascular patterning and endothelial polarization.
引用
收藏
页码:2055 / 2068
页数:14
相关论文
共 41 条
[1]   Bacterial toxins block endothelial wound repair - Evidence that Rho GTPases control cytoskeletal rearrangements in migrating endothelial cells [J].
Aepfelbacher, M ;
Essler, M ;
Huber, E ;
Sugai, M ;
Weber, SC .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 1997, 17 (09) :1623-1629
[2]   Development of endothelial cell lines from embryonic stem cells - A tool for studying genetically manipulated endothelial cells in vitro [J].
Balconi, G ;
Spagnuolo, R ;
Dejana, E .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2000, 20 (06) :1443-1451
[3]   Reduced choroidal neovascular membrane formation in matrix metalloproteinase-2-deficient mice [J].
Berglin, L ;
Sarman, S ;
van der Ploeg, I ;
Steen, B ;
Ming, Y ;
Itohara, S ;
Seregard, S ;
Kvanta, A .
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2003, 44 (01) :403-408
[4]   PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis [J].
Bostrom, H ;
Willetts, K ;
Pekny, M ;
Leveen, P ;
Lindahl, P ;
Hedstrand, H ;
Pekna, M ;
Hellstrom, M ;
GebreMedhin, S ;
Schalling, M ;
Nilsson, M ;
Kurland, S ;
Tornell, J ;
Heath, JK ;
Betsholtz, C .
CELL, 1996, 85 (06) :863-873
[5]   Angiomotin regulates endothelial cell-cell junctions and cell motility [J].
Bratt, A ;
Birot, O ;
Sinha, I ;
Veitonmäki, N ;
Aase, K ;
Ernkvist, M ;
Holmgren, L .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (41) :34859-34869
[6]   Angiomotin belongs to a novel protein family with conserved coiled-coil and PDZ binding domains [J].
Bratt, A ;
Wilson, WJ ;
Troyanovsky, B ;
Aase, K ;
Kessler, R ;
Van Meir, EG ;
Holmgren, L .
GENE, 2002, 298 (01) :69-77
[7]   Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele [J].
Carmeliet, P ;
Ferreira, V ;
Breier, G ;
Pollefeyt, S ;
Kieckens, L ;
Gertsenstein, M ;
Fahrig, M ;
Vandenhoeck, A ;
Harpal, K ;
Eberhardt, C ;
Declercq, C ;
Pawling, J ;
Moons, L ;
Collen, D ;
Risau, W ;
Nagy, A .
NATURE, 1996, 380 (6573) :435-439
[8]  
Childs S, 2002, DEVELOPMENT, V129, P973
[9]   Distinct genetic interactions between multiple Vegf receptors are required for development of different blood vessel types in zebrafish [J].
Covassin, LD ;
Villefranc, JA ;
Kacergis, MC ;
Weinstein, BM ;
Lawson, ND .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (17) :6554-6559
[10]  
Emkvist M., 2006, FEBS J, V273, P2000