title: Fibroblast growth factor signals regulate a wave of Hedgehog activation that is essential for coronary vascular development.
abstract: Myocardial infarction and ischemic heart disease are the leading cause of death in the industrial world. Therapies employed for treating these diseases are aimed at promoting increased blood flow to cardiac tissue. Pharmacological induction of new coronary growth has recently been explored, however, clinical trials with known proangiogenic factors have been disappointing. To identify novel therapeutic targets, we have explored signaling pathways that govern embryonic coronary development. Using a combination of genetically engineered mice and an organ culture system, we identified novel roles for fibroblast growth factor (FGF) and Hedgehog (HH) signaling in coronary vascular development. We show that FGF signals promote coronary growth indirectly by signaling to the cardiomyoblast through redundant function of Fgfr1 and Fgfr2. Myocardial FGF signaling triggers a wave of HH activation that is essential for vascular endothelial growth factor (Vegf)-A, Vegf-B, Vegf-C, and angiopoietin-2 (Ang2) expression. We demonstrate that HH is necessary for coronary vascular development and activation of HH signaling is sufficient to promote coronary growth and to rescue coronary defects due to loss of FGF signaling. These studies implicate HH signaling as an essential regulator of coronary vascular development and as a potential therapeutic target for coronary neovascularization. Consistent with this, activation of HH signaling in the adult heart leads to an increase in coronary vessel density.
authors.affiliation: Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, Missouri 63110, USA.
authors.forename: Kory J
authors.initials: KJ
authors.lastname: Lavine
authors.forename: Andrew C
authors.initials: AC
authors.lastname: White
authors.forename: Changwon
authors.initials: C
authors.lastname: Park
authors.forename: Craig S
authors.initials: CS
authors.lastname: Smith
authors.forename: Kyunghee
authors.initials: K
authors.lastname: Choi
authors.forename: Fanxin
authors.initials: F
authors.lastname: Long
authors.forename: Chi-chung
authors.initials: CC
authors.lastname: Hui
authors.forename: David M
authors.initials: DM
authors.lastname: Ornitz
mesh_terms: D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003331:Coronary Vessels / Q000254:growth & development*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D051525:Fibroblast Growth Factor 9 / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000254:growth & development; D053823:Hedgehog Proteins; D051379:Mice; D032386:Myoblasts, Cardiac / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D042682:Angiopoietins; C496460:Fgf9 protein, mouse; D051525:Fibroblast Growth Factor 9; D053823:Hedgehog Proteins; D012333:RNA, Messenger; C465570:Shh protein, mouse; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D005346:Fibroblast Growth Factors