Endothelial fibroblast growth factor receptor signaling is required for vascular remodeling following cardiac ischemia-reperfusion injury

Stacey L. House, Angela M. Castro, Traian S. Lupu, Carla Weinheimer, Craig Smith, Attila Kovacs, David M. Ornitz

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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 in-activated the Fgfr1 and Fgfr2 genes in endothelial cells with Tie2-Cre (Tie2-Cre, Fgfr1f/f, Fgfr2f/f DCKO mice). Tie2-Cre, Fgfr1f/f, Fgfr2f/f DCKO mice had normal baseline cardiac morphometry, function, and vessel density. When subjected to closed-chest, regional cardiac ischemia-reperfusion injury, Tie2-Cre, Fgfr1f/f, Fgfr2f/f DCKO mice showed a significantly increased hypokinetic area at 7 days, but not 1 day, after reperfusion. Tie2-Cre, Fgfr1f/f, Fgfr2f/f DCKO mice also showed significantly worsened cardiac function compared with con-trols 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, Fgfr1f/f, Fgfr2f/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 recov-ery and vascular remodeling following in vivo cardiac ischemia-reperfusion injury, without affecting the cardiac hypertrophic re-sponse. This study suggests the potential for therapeutic benefit from activation of endothelial FGFR pathways following ischemic injury to the heart.

Original languageEnglish
Pages (from-to)H559-H571
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume310
Issue number5
DOIs
StatePublished - Mar 2016

Keywords

  • Cardiac ischemia-reperfusion injury
  • Endothelium
  • Fibroblast growth factor
  • Myocardial infarction
  • Vascular remodeling

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