title: Endothelial fibroblast growth factor receptor signaling is required for vascular remodeling following cardiac ischemia-reperfusion injury.
abstract: Fibroblast growth factor (FGF) signaling is cardioprotective in various models of myocardial infarction. FGF receptors (FGFRs) are expressed in multiple cell types in the adult heart, but the cell type-specific FGFR signaling that mediates different cardioprotective endpoints is not known. To determine the requirement for FGFR signaling in endothelium in cardiac ischemia-reperfusion injury, we conditionally inactivated the Fgfr1 and Fgfr2 genes in endothelial cells with Tie2-Cre (Tie2-Cre, Fgfr1(f/f), Fgfr2(f/f) DCKO mice). Tie2-Cre, Fgfr1(f/f), Fgfr2(f/f) DCKO mice had normal baseline cardiac morphometry, function, and vessel density. When subjected to closed-chest, regional cardiac ischemia-reperfusion injury, Tie2-Cre, Fgfr1(f/f), Fgfr2(f/f) DCKO mice showed a significantly increased hypokinetic area at 7 days, but not 1 day, after reperfusion. Tie2-Cre, Fgfr1(f/f), Fgfr2(f/f) DCKO mice also showed significantly worsened cardiac function compared with controls at 7 days but not 1 day after reperfusion. Pathophysiological analysis showed significantly decreased vessel density, increased endothelial cell apoptosis, and worsened tissue hypoxia in the peri-infarct area at 7 days following reperfusion. Notably, Tie2-Cre, Fgfr1(f/f), Fgfr2(f/f) DCKO mice showed no impairment in the cardiac hypertrophic response. These data demonstrate an essential role for FGFR1 and FGFR2 in endothelial cells for cardiac functional recovery and vascular remodeling following in vivo cardiac ischemia-reperfusion injury, without affecting the cardiac hypertrophic response. This study suggests the potential for therapeutic benefit from activation of endothelial FGFR pathways following ischemic injury to the heart.
authors.affiliation: Division of Emergency Medicine, Washington University in St. Louis School of Medicine, St. Louis, Missouri; Department of Developmental Biology, Washington University in St. Louis School of Medicine, St. Louis, Missouri staceyhouse@wustl.edu.
authors.forename: Stacey L
authors.initials: SL
authors.lastname: House
authors.affiliation: Department of Developmental Biology, Washington University in St. Louis School of Medicine, St. Louis, Missouri.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Castro
authors.affiliation: Division of Emergency Medicine, Washington University in St. Louis School of Medicine, St. Louis, Missouri; Department of Developmental Biology, Washington University in St. Louis School of Medicine, St. Louis, Missouri.
authors.forename: Traian S
authors.initials: TS
authors.lastname: Lupu
authors.affiliation: Center for Cardiovascular Research, Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, Missouri; and.
authors.forename: Carla
authors.initials: C
authors.lastname: Weinheimer
authors.affiliation: Department of Developmental Biology, Washington University in St. Louis School of Medicine, St. Louis, Missouri.
authors.forename: Craig
authors.initials: C
authors.lastname: Smith
authors.affiliation: Center for Cardiovascular Research, Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, Missouri; and.
authors.forename: Attila
authors.initials: A
authors.lastname: Kovacs
authors.affiliation: Department of Developmental Biology, Washington University in St. Louis School of Medicine, St. Louis, Missouri.
authors.forename: David M
authors.identifier: http://orcid.org/0000-0003-1592-7629
authors.initials: DM
authors.lastname: Ornitz
mesh_terms: D000818:Animals; D017209:Apoptosis; D002196:Capillaries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function; D015398:Signal Transduction; D013318:Stroke Volume; D013997:Time Factors; D066253:Vascular Remodeling; D016277:Ventricular Function, Left
chemical_list: C496349:Fgfr1 protein, mouse; C496354:Fgfr2 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2
keywords: cardiac ischemia-reperfusion injury; endothelium; fibroblast growth factor; myocardial infarction; vascular remodeling