Convergence of Notch and beta-catenin signaling induces arterial fate in vascular progenitors.
Molecular mechanisms controlling arterial-venous specification have not been fully elucidated. Previously, we established an embryonic stem cell differentiation system and demonstrated that activation of cAMP signaling together with VEGF induces arterial endothelial cells (ECs) from Flk1(+) vascular progenitor cells. Here, we show novel arterial specification machinery regulated by Notch and beta-catenin signaling. Notch and GSK3beta-mediated beta-catenin signaling were activated downstream of cAMP through phosphatidylinositol-3 kinase. Forced activation of Notch and beta-catenin with VEGF completely reconstituted cAMP-elicited arterial EC induction, and synergistically enhanced target gene promoter activity in vitro and arterial gene expression during in vivo angiogenesis. A protein complex with RBP-J, the intracellular domain of Notch, and beta-catenin was formed on RBP-J binding sites of arterial genes in arterial, but not venous ECs. This molecular machinery for arterial specification leads to an integrated and more comprehensive understanding of vascular signaling.
Yamamizu
Kohei
K
Laboratory of Stem Cell Differentiation, Stem Cell Research Center, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
Matsunaga
Taichi
T
Uosaki
Hideki
H
Fukushima
Hiroyuki
H
Katayama
Shiori
S
Hiraoka-Kanie
Mina
M
Mitani
Kohnosuke
K
Yamashita
Jun K
JK
D000818:Animals; D001158:Arteries / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D014680:Veins / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D015415:Biomarkers; D000242:Cyclic AMP; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051880:Receptors, Notch; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D051176:beta Catenin; C497571:Rbpj protein, mouse; C000605507:Gsk3b protein, mouse
Nature. 2001 Nov 8;414(6860):216-20
11700560
Development. 1996 May;122(5):1373-83
8625826
Genes Dev. 2008 Sep 1;22(17):2308-41
18765787
Nat Cell Biol. 2001 Nov;3(11):1009-13
11715022
J Biol Chem. 2001 May 25;276(21):17686-92
11278468
Development. 2004 Mar;131(5):965-73
14973298
Blood. 2005 Apr 15;105(8):3155-61
15626744
Nature. 2005 Jun 16;435(7044):959-63
15959515
Nature. 1995 Dec 21-28;378(6559):785-9
8524413
Methods Mol Med. 2002;69:389-414
11987791
Genes Dev. 1998 Dec 1;12(23):3728-40
9851979
Proc Natl Acad Sci U S A. 2005 Jan 25;102(4):1076-81
15644447
Cell. 2006 Nov 3;127(3):469-80
17081971
Exp Cell Res. 1999 Oct 10;252(1):13-9
10502395
J Biol Chem. 1999 Jun 18;274(25):17934-40
10364240
Nat Immunol. 2005 Mar;6(3):314-22
15665828
Blood. 2009 Oct 22;114(17):3707-16
19706882
Bioinformatics. 2000 Nov;16(11):1046-7
11159318
Genes Dev. 2004 Oct 15;18(20):2474-8
15466159
Cell. 2002 Oct 18;111(2):241-50
12408868
Development. 2006 Nov;133(22):4427-38
17035290
Development. 2004 Jun;131(12):2791-801
15142975
Development. 2001 Jan;128(1):25-33
11092808
Dev Cell. 2007 Mar;12(3):415-29
17336907
Angiogenesis. 2002;5(1-2):1-9
12549854
EMBO J. 1999 Apr 15;18(8):2196-207
10205173
Cell. 1998 May 29;93(5):741-53
9630219
Nature. 1998 Jun 11;393(6685):591-4
9634237
Curr Biol. 1996 Nov 1;6(11):1363-7
8939593
Genes Dev. 1999 Feb 1;13(3):295-306
9990854
Development. 1996 Nov;122(11):3343-53
8951051
Blood. 2009 May 28;113(22):5680-8
19144989
Hum Mol Genet. 1999 May;8(5):723-30
10196361
FASEB J. 2005 Sep;19(11):1534-6
16033809
Circ Res. 2002 Jun 28;90(12):1243-50
12089061
Development. 2005 Apr;132(8):1819-30
15772135
Mech Dev. 2001 Oct;108(1-2):161-4
11578869
Mech Dev. 2006 Jul;123(7):570-9
16822655
Development. 2009 Feb;136(4):595-603
19168675
Nature. 2000 Nov 2;408(6808):92-6
11081514
Science. 1999 Apr 30;284(5415):770-6
10221902
Science. 2005 Mar 25;307(5717):1904-9
15790842
Genes Dev. 2004 Oct 15;18(20):2469-73
15466160
Development. 2001 Oct;128(19):3675-83
11585794
Cell Res. 2005 Jan;15(1):28-32
15686623
J Biol Chem. 2002 Nov 1;277(44):41888-96
12167628
Mol Cell Biol. 2008 Dec;28(24):7427-41
18852283
J Cell Biol. 2003 Sep 15;162(6):1111-22
12975353
Arterioscler Thromb Vasc Biol. 2006 Sep;26(9):1977-84
16809546
Nucleic Acids Res. 1994 Nov 11;22(22):4673-80
7984417