VEGF and FGF prime vascular tube morphogenesis and sprouting directed by hematopoietic stem cell cytokines.
Here, we demonstrate a novel, direct-acting, and synergistic role for 3 hematopoietic stem cell cytokines: stem cell factor, interleukin-3, and stromal derived factor-1α, in controlling human endothelial cell (EC) tube morphogenesis, sprouting, and pericyte-induced tube maturation under defined serum-free conditions in 3-dimensional matrices. Angiogenic cytokines such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) alone or VEGF/FGF combinations do not support these responses. In contrast, VEGF and FGF prime EC responses to hematopoietic cytokines via up-regulation of c-Kit, IL-3Rα, and C-X-C chemokine receptor type 4 from either human ECs or embryonic quail vessel explants. In support of these findings, EC Runx1 is demonstrated to be critical in coordinating vascular morphogenic responses by controlling hematopoietic cytokine receptor expression. Combined blockade of hematopoietic cytokines or their receptors in vivo leads to blockade of developmental vascularization in quail embryos manifested by vascular hemorrhage and disrupted vascular remodeling events in multiple tissue beds. This work demonstrates a unique role for hematopoietic stem cell cytokines in vascular tube morphogenesis and sprouting and further demonstrates a novel upstream priming role for VEGF and FGF to facilitate the action of promorphogenic hematopoietic cytokines.
Department of Medical Pharmacology and Physiology, School of Medicine, Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, MO 65212, USA.
Amber N
AN
Stratman
Michael J
MJ
Davis
George E
GE
Davis
D000818:Animals; D002196:Capillaries / Q000187:drug effects* / Q000254:growth & development; D002417:Cattle; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology*; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D005346:Fibroblast Growth Factors / Q000494:pharmacology* / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011554:Pseudopodia / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D011784:Quail / Q000196:embryology / Q000502:physiology; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology* / Q000502:physiology
D016207:Cytokines; D042461:Vascular Endothelial Growth Factor A; D005346:Fibroblast Growth Factors
Leukemia. 1998 Jul;12(7):1089-98
9665195
Cell Stem Cell. 2008 Dec 4;3(6):625-36
19041779
Dev Cell. 2006 Aug;11(2):171-80
16890157
Blood. 2010 Jun 17;115(24):5102-10
20154215
Cell Signal. 2005 Apr;17(4):497-506
15601627
Science. 2009 Nov 27;326(5957):1216-9
19965464
Semin Hematol. 2007 Jul;44(3):193-202
17631183
Cell. 1985 Sep;42(2):469-77
2411423
Blood. 1992 Feb 1;79(3):634-41
1370637
Circ Res. 2008 Mar 28;102(6):637-52
18369162
Development. 1999 Jun;126(11):2563-75
10226014
Exp Cell Res. 1996 Apr 10;224(1):39-51
8612690
Methods Enzymol. 2008;443:83-101
18772012
J Cell Biol. 2003 Jun 23;161(6):1163-77
12810700
Genes Dev. 2009 Oct 1;23(19):2272-7
19797767
Nat Rev Drug Discov. 2009 Mar;8(3):235-53
19247306
Blood. 2000 Nov 1;96(9):3078-85
11049987
Blood. 1996 Jan 1;87(1):67-72
8547678
Haematologica. 2010 Jun;95(6):875-83
20007140
Cell Stem Cell. 2010 Mar 5;6(3):251-64
20207228
Nature. 2010 Mar 4;464(7285):108-11
20154733
Development. 2002 Apr;129(8):2015-30
11934867
Development. 1998 Nov;125(22):4575-83
9778515
Nat Med. 2006 May;12(5):557-67
16648859
Stem Cells. 2009 Jul;27(7):1616-24
19544462
Immunity. 2004 Jul;21(1):31-41
15345218
Nat Cell Biol. 2010 Nov;12(11):1046-56
20972423
Dev Biol. 1999 Sep 15;213(2):442-56
10479460
Nature. 2009 Feb 12;457(7231):887-91
19129762
Int J Biochem Cell Biol. 2007;39(11):1995-8
17350321
Development. 2010 Dec;137(23):3941-52
20980401
Circ Res. 2005 Nov 25;97(11):1093-107
16306453
Blood. 2010 Nov 25;116(22):4720-30
20739660
Blood. 2009 Dec 3;114(24):5091-101
19822899
J Immunol. 1998 Oct 1;161(7):3652-8
9759889
BioDrugs. 2009;23(6):377-89
19894779
Int J Dev Biol. 2008;52(1):87-92
18033676
Nature. 2010 Mar 4;464(7285):116-20
20154729
Curr Opin Hematol. 2008 May;15(3):215-20
18391788
Development. 1996 Oct;122(10):3023-33
8898216
J Cell Sci. 2009 Jun 1;122(Pt 11):1812-22
19435802
Blood. 2005 May 1;105(9):3502-11
15644413
Blood. 2006 Jan 1;107(1):106-10
16174759
Cell. 2006 Jan 13;124(1):175-89
16413490
Blood. 2004 Jul 15;104(2):495-501
14976047
Curr Opin Cell Biol. 2009 Apr;21(2):154-65
19230644
Organogenesis. 2008 Oct;4(4):257-63
19337406
Curr Drug Metab. 2009 Jun;10(5):470-81
19689244
Circ Res. 2008 Oct 10;103(8):784-95
18845818
Nature. 2009 Feb 12;457(7231):896-900
19212410