Autocrine VEGF signaling is required for vascular homeostasis.
Vascular endothelial growth factor (VEGF) is essential for developmental and pathological angiogenesis. Here we show that in the absence of any pathological insult, autocrine VEGF is required for the homeostasis of blood vessels in the adult. Genetic deletion of vegf specifically in the endothelial lineage leads to progressive endothelial degeneration and sudden death in 55% of mutant mice by 25 weeks of age. The phenotype is manifested without detectable changes in the total levels of VEGF mRNA or protein, indicating that paracrine VEGF could not compensate for the absence of endothelial VEGF. Furthermore, wild-type, but not VEGF null, endothelial cells showed phosphorylation of VEGFR2 in the absence of exogenous VEGF. Activation of the receptor in wild-type cells was suppressed by small molecule antagonists but not by extracellular blockade of VEGF. These results reveal a cell-autonomous VEGF signaling pathway that holds significance for vascular homeostasis but is dispensable for the angiogenic cascade.
Lee
Sunyoung
S
Department of Molecular, Cellular and Developmental Biology, Jonsson Comprehensive Cancer Center and Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA.
Chen
Tom T
TT
Barber
Chad L
CL
Jordan
Maria C
MC
Murdock
Jared
J
Desai
Sharina
S
Ferrara
Napoleone
N
Nagy
Andras
A
Roos
Kenneth P
KP
Iruela-Arispe
M Luisa
ML
D000818:Animals; D017209:Apoptosis; D019898:Autocrine Communication; D001808:Blood Vessels / Q000166:cytology; D015687:Cell Hypoxia; D002470:Cell Survival; D002478:Cells, Cultured; D003035:Cobalt / Q000633:toxicity; D003433:Crosses, Genetic; D004452:Echocardiography; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006706:Homeostasis; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008954:Models, Biological; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013686:Telemetry; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D003035:Cobalt; D040301:Vascular Endothelial Growth Factor Receptor-2; C018021:cobaltous chloride
Development. 2000 Sep;127(18):3941-6
10952892
Hum Mol Genet. 2005 Jul 15;14(14):1921-33
15917272
J Biol Chem. 2001 Jul 20;276(29):26969-79
11350975
Nat Med. 2001 Sep;7(9):987-9
11533692
J Mol Cell Cardiol. 2001 Sep;33(9):1673-90
11549346
J Cardiovasc Electrophysiol. 2001 Sep;12(9):1089-91
11573703
Development. 2002 Apr;129(8):1881-92
11934854
Nature. 2002 Jun 27;417(6892):954-8
12087404
J Clin Oncol. 2003 Jan 1;21(1):60-5
12506171
Dev Biol. 2003 Mar 1;255(1):77-98
12618135
J Clin Invest. 2003 Mar;111(5):707-16
12618525
Nat Med. 2004 Feb;10(2):145-7
14745444
N Engl J Med. 2004 Jun 3;350(23):2335-42
15175435
Am J Pathol. 2004 Jul;165(1):35-52
15215160
Dev Cell. 2004 Jul;7(1):107-16
15239958
J Immunol. 1979 Jan;122(1):166-74
762415
Science. 1983 Feb 25;219(4587):983-5
6823562
Science. 1985 Mar 1;227(4690):1059-61
3975602
J Biol Chem. 1985 Oct 5;260(22):12351-8
2995372
Circulation. 1994 Aug;90(2):1033-43
8044917
J Cell Biol. 1995 May;129(4):895-8
7538139
J Biol Chem. 1995 Dec 29;270(52):31189-95
8537383
Nature. 1996 Apr 4;380(6573):435-9
8602241
Nature. 1996 Apr 4;380(6573):439-42
8602242
Circulation. 1996 Sep 1;94(5):1109-17
8790053
EXS. 1997;79:233-69
9002222
Cell. 1998 Mar 20;92(6):735-45
9529250
Curr Top Microbiol Immunol. 1999;237:97-132
9893348
Nat Genet. 1999 Jan;21(1):70-1
9916792
Development. 1999 Mar;126(6):1149-59
10021335
Dev Biol. 1999 Aug 15;212(2):307-22
10433823
J Thromb Haemost. 2005 Aug;3(8):1835-42
16102050
Mol Genet Metab. 2005 Sep-Oct;86(1-2):233-43
15979918
Nature. 2005 Dec 15;438(7070):967-74
16355214
Am J Physiol Heart Circ Physiol. 2006 Feb;290(2):H560-76
16172168
Nat Clin Pract Oncol. 2006 Jan;3(1):24-40
16407877
Am J Pathol. 2006 Feb;168(2):639-48
16436677
Dev Dyn. 2006 Mar;235(3):759-67
16450386
Exp Cell Res. 2006 Mar 10;312(5):522-6
16430882
J Cell Biol. 2006 Apr 10;173(1):95-106
16606693
Heart. 2006 Aug;92(8):1101
16844860
J Cell Biol. 2006 Aug 14;174(4):593-604
16893970
Trends Cell Biol. 2006 Oct;16(10):514-21
16949287
Mol Cell Biol. 2006 Dec;26(23):8928-41
17000777
Science. 2006 Nov 17;314(5802):1135-9
17110576
Curr Biol. 2006 Nov 21;16(22):2228-33
17088062
Annu Rev Med. 2007;58:491-504
17052163
Pathophysiol Haemost Thromb. 2003 Sep-2004 Dec;33(5-6):256-61
15692226
Pathophysiol Haemost Thromb. 2003 Sep-2004 Dec;33(5-6):445-8
15692258
J Clin Oncol. 2005 Feb 10;23(5):1011-27
15585754
J Cell Biol. 2005 May 23;169(4):681-91
15911882