Abstract 101: Endothelial-Specific Fibroblast Growth Factor Receptor 1 and 2 Deletion Impairs Vascular Remodeling and Recovery in an In Vivo Closed-Chest Model of Cardiac Ischemia-Reperfusion Injury
Introduction: 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 which mediates different cardioprotective endpoints is currently unknown.
Hypothesis: We hypothesize that endothelial FGFR signaling is essential for vascular remodeling after cardiac ischemia-reperfusion (IR) injury.
Methods: We have generated mice with a conditional ablation of the Fgfr1 and Fgfr2 genes in endothelial cells (Tie2-Cre, Fgfr1f/f, Fgfr2f/f). These mice and littermate controls were subjected to a clinically relevant, in vivo, closed-chest model of cardiac IR injury which includes 90 minutes of occlusion of the left anterior descending artery followed by reperfusion for 7 days. Echocardiography was performed at baseline, day 1, and day 7 of reperfusion, and histological staining was performed on day 7.
Results:Tie2-Cre, Fgfr1f/f, Fgfr2f/f mice had no baseline abnormalities in cardiac morphometry or function. When subjected to closed-chest, regional cardiac IR injury, Tie2-Cre, Fgfr1f/f, Fgfr2f/f mice showed significantly increased infarct size compared to controls at 7 days (37±3% vs. 15±5%, p<0.05) but not 1 day after reperfusion. Tie2-Cre, Fgfr1f/f, Fgfr2f/f mice also showed significantly worsened cardiac function (ejection fraction, stroke volume, and fractional shortening) compared to controls at 7 days (p<0.05) but not 1 day after reperfusion. Myocyte cross-sectional area measurement showed no impairment in the cardiac hypertrophic response in the Tie2-Cre, Fgfr1f/f, Fgfr2f/f mice. Tie2-Cre, Fgfr1f/f, Fgfr2f/f mice have normal vessel density in the non-injured state, but after cardiac IR injury, Tie2-Cre, Fgfr1f/f, Fgfr2f/f hearts showed significantly decreased vessel density (both capillaries and smooth muscle actin containing vessels, p<0.05) compared to controls in the peri-infarct area.
Conclusions: Ablation of FGFR1 and FGFR2 in endothelial cells results in impaired vascular remodeling, worsened cardiac functional recovery, and increased infarct size without affecting the cardiac hypertrophic response in an in vivo, closed-chest model of cardiac IR injury.
- © 2012 by American Heart Association, Inc.