title: Epicardial HIF signaling regulates vascular precursor cell invasion into the myocardium.
abstract: During cardiogenesis, a subset of epicardial cells undergoes epithelial-mesenchymal-transition (EMT) and the resulting epicardial-derived cells (EPDCs) contribute to the formation of coronary vessels. Our previous data showed hypoxia inducible factor-1α (HIF-1α) expression at specific sites within the epicardium and support a link between hypoxia inducible factors (HIFs) and the patterning of coronary vasculogenesis. To better understand the autocrine role of HIFs in the epicardium, we transduced adenovirus mediated expression of constitutively active HIF-1α (AdcaHIF1α) into the embryonic avian epicardium where the vascular precursors reside. We found that introducing caHIF1α into the epicardial mesothelium prevented EPDCs from proper migration into the myocardium. In vitro collagen gel assays and ex vivo organ culture data further confirmed that infection with AdcaHIF1α impaired the ability of EPDCs to invade. However, the proficiency of epicardial cells to undergo EMT was enhanced while the movement of EPDCs within the sub-epicardium and their differentiation into smooth muscle cells were not disrupted by caHIF1α. We also showed that the transcript level of Flt-1 (VEGFR1), which can act as a VEGF signaling inhibitor, increased several fold after introducing caHIF1α into epicardial cells. Blocking the activation of the VEGF pathway in epicardial cells recapitulated the inhibition of EPDC invasion. These results suggest that caHIF1α mediated up-regulation of Flt-1, which blocks the activation of the VEGF pathway, is responsible for the inhibition of EPDC myocardial migration. In conclusion, our studies demonstrate that HIF signaling potentially regulates the degree of epicardial EMT and the extent of EPDC migration into the myocardium, both of which are likely critical in patterning the coronary vasculature during early cardiac vasculogenesis. These signals could explain why the larger coronaries appear and remain on the epicardial surface.
authors: Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University School of Medicine, Cleveland, OH 44106-6011, USA.
authors: Jiayi
authors: J
authors: Tao
authors: Yongqiu
authors: Y
authors: Doughman
authors: Ke
authors: K
authors: Yang
authors: Diana
authors: D
authors: Ramirez-Bergeron
authors: Michiko
authors: M
authors: Watanabe
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D002645:Chickens; D003094:Collagen / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D009206:Myocardium / Q000378:metabolism*; D010496:Pericardium / Q000378:metabolism*; D011784:Quail; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D003094:Collagen; D040281:Vascular Endothelial Growth Factor Receptor-1
references: Cell Mol Life Sci. 2007 Mar;64(6):692-703
references: 17380310
references: Anat Rec (Hoboken). 2008 Oct;291(10):1187-99
references: 18727106
references: Circ Res. 2003 Nov 28;93(11):1074-81
references: 14576200
references: Genes Dev. 1998 Jan 15;12(2):149-62
references: 9436976
references: Dev Dyn. 1999 Sep;216(1):28-36
references: 10474163
references: Dev Dyn. 2009 Feb;238(2):423-30
references: 19161222
references: Circ Res. 1992 Jul;71(1):40-50
references: 1606667
references: J Biochem Mol Biol. 2006 Sep 30;39(5):469-78
references: 17002866
references: FASEB J. 2002 Aug;16(10):1151-62
references: 12153983
references: Circ Res. 2006 Apr 14;98(7):947-53
references: 16527987
references: Adv Anat Embryol Cell Biol. 2003;167:III-VIII, 1-111
references: 12557422
references: Development. 1997 Nov;124(21):4405-13
references: 9334288
references: Stem Cells. 2001;19(4):279-86
references: 11463947
references: Mol Cell Biol. 1996 Sep;16(9):4604-13
references: 8756616
references: Am J Pathol. 2004 May;164(5):1531-5
references: 15111299
references: Blood. 2006 Sep 15;108(6):1821-9
references: 16705092
references: Indian J Pediatr. 1998 Mar-Apr;65(2):217-29
references: 10771967
references: Circ Res. 2010 Mar 19;106(5):818-32
references: 20299672
references: Dev Biol. 2001 Jun 1;234(1):204-15
references: 11356030
references: Dev Biol. 2010 Nov 15;347(2):325-36
references: 20816797
references: EMBO J. 1998 Jun 1;17(11):3005-15
references: 9606183
references: Stem Cells. 2010 Apr;28(4):799-809
references: 20135683
references: Cell Stem Cell. 2010 Aug 6;7(2):150-61
references: 20682444
references: Dev Dyn. 2006 Jan;235(1):50-9
references: 16245329
references: Nature. 1997 Mar 27;386(6623):403-7
references: 9121557
references: Nat Rev Mol Cell Biol. 2008 Apr;9(4):285-96
references: 18285802
references: Dev Dyn. 2006 Mar;235(3):723-33
references: 16444736
references: Dev Biol. 2003 May 15;257(2):315-28
references: 12729561
references: Trends Cardiovasc Med. 2004 Aug;14(6):247-51
references: 15451517
references: Dev Dyn. 2009 Oct;238(10):2688-700
references: 19777592
references: Blood. 1999 Jun 15;93(12):4284-92
references: 10361126
references: Pediatr Clin North Am. 2004 Oct;51(5):1273-88
references: 15331284
references: Dev Dyn. 2006 Jan;235(1):115-23
references: 16028272
references: J Biol Chem. 1997 Sep 19;272(38):23659-67
references: 9295307
references: Circ Res. 1993 Sep;73(3):559-68
references: 8348697
references: Dev Cell. 2009 Sep;17(3):377-86
references: 19758562
references: Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9504-8
references: 1409660
references: Genes Dev. 2000 Dec 15;14(24):3191-203
references: 11124810
references: Anat Rec A Discov Mol Cell Evol Biol. 2004 Jan;276(1):43-57
references: 14699633
references: Cardiovasc Res. 1996 Feb;31 Spec No:E86-95
references: 8681350
references: Dev Dyn. 2008 Feb;237(2):366-76
references: 18213583
references: Anat Rec. 1981 Sep;201(1):157-68
references: 7305017
references: Adv Exp Med Biol. 2003;543:139-49
references: 14713119
references: J Cell Biol. 2006 Mar 27;172(7):973-81
references: 16567498
references: Dev Biol. 2006 Nov 15;299(2):489-504
references: 17026982
references: Int J Microcirc Clin Exp. 1991 Nov;10(4):359-71
references: 1778679
references: Nature. 2006 Oct 26;443(7114):993-7
references: 17051153
references: Dev Cell. 2009 Dec;17(6):755-73
references: 20059947
references: Sci STKE. 2005 Oct 18;2005(306):re12
references: 16234508
references: Angiogenesis. 2012 Sep;15(3):409-20
references: 22484908
references: Circulation. 1999 Aug 10;100(6):583-6
references: 10441093
references: J Biol Chem. 2003 Feb 28;278(9):7520-30
references: 12464608
references: J Cell Biol. 2008 Jun 2;181(5):847-58
references: 18504303
references: Cardiovasc Toxicol. 2013 Jun;13(2):161-7
references: 23264063
references: Am J Anat. 1989 Feb;184(2):129-38
references: 2712004
references: Science. 1992 Feb 21;255(5047):989-91
references: 1312256
references: Clin Anat. 2011 Sep;24(6):675-83
references: 21751254