Small Vessels–Big Problems: Novel Insights into Microvascular Mechanisms of Diseases Endothelial fibroblast growth factor receptor signaling is required for vascular remodeling following cardiac ischemia-reperfusion injury

Endothelial fibroblast growth factor receptor signaling is required for vascular remodeling following cardiac ischemia-reperfusion in- jury. Am growth factor (FGF) signaling is cardioprotective in various models of myocardial infarction. FGF receptors (FGFRs) are expressed in mul- tiple 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, 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 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, 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. Impaired vascular deficient

[1]  N. Itoh,et al.  The Fibroblast Growth Factor signaling pathway , 2015, Wiley interdisciplinary reviews. Developmental biology.

[2]  D. Ornitz,et al.  Fibroblast growth factor 2 is an essential cardioprotective factor in a closed‐chest model of cardiac ischemia‐reperfusion injury , 2015, Physiological reports.

[3]  Sunday S. Oladipupo,et al.  Endothelial cell FGF signaling is required for injury response but not for vascular homeostasis , 2014, Proceedings of the National Academy of Sciences.

[4]  Peter Libby,et al.  Cardiovascular remodelling in coronary artery disease and heart failure , 2014, The Lancet.

[5]  Yao Sun,et al.  Acidic and basic fibroblast growth factors involved in cardiac angiogenesis following infarction. , 2011, International journal of cardiology.

[6]  S. Kopetz,et al.  Beyond VEGF: Inhibition of the Fibroblast Growth Factor Pathway and Antiangiogenesis , 2011, Clinical Cancer Research.

[7]  T. Doetschman,et al.  Fibroblast Growth Factor 2 Mediates Isoproterenol-induced Cardiac Hypertrophy through Activation of the Extracellular Regulated Kinase. , 2010, Molecular and cellular pharmacology.

[8]  H. Matsubara,et al.  Endothelium-targeted overexpression of constitutively active FGF receptor induces cardioprotection in mice myocardial infarction. , 2009, Journal of molecular and cellular cardiology.

[9]  Yao Sun,et al.  Reactive oxygen species promote angiogenesis in the infarcted rat heart , 2009, International journal of experimental pathology.

[10]  W. Frishman,et al.  Therapeutic Angiogenesis: A New Treatment Approach for Ischemic Heart Disease—Part II , 2008, Cardiology in review.

[11]  E. Feigl,et al.  Fibroblast growth factor-2 regulates myocardial infarct repair: effects on cell proliferation, scar contraction, and ventricular function. , 2007, The American journal of pathology.

[12]  L. Luo,et al.  A global double‐fluorescent Cre reporter mouse , 2007, Genesis.

[13]  E. Kardami,et al.  Fibroblast growth factor-2 and cardioprotection , 2007, Heart Failure Reviews.

[14]  C. Simopoulos,et al.  Intramyocardial injection of low-dose basic fibroblast growth factor or vascular endothelial growth factor induces angiogenesis in the infarcted rabbit myocardium. , 2007, Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology.

[15]  Jay W. Shin,et al.  Prox1 promotes lineage-specific expression of fibroblast growth factor (FGF) receptor-3 in lymphatic endothelium: a role for FGF signaling in lymphangiogenesis. , 2005, Molecular biology of the cell.

[16]  M. Varia,et al.  Evidence that involucrin, a marker for differentiation, is oxygen regulated in human squamous cell carcinomas , 2004, British Journal of Cancer.

[17]  T. Doetschman,et al.  Cardiac-Specific Overexpression of Fibroblast Growth Factor-2 Protects Against Myocardial Dysfunction and Infarction in a Murine Model of Low-Flow Ischemia , 2003, Circulation.

[18]  A. Bikfalvi,et al.  The role of fibroblast growth factors in vascular development. , 2002, Trends in molecular medicine.

[19]  J. Saffitz,et al.  Echocardiographic evaluation of ventricular remodeling in a mouse model of myocardial infarction. , 2002, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[20]  T. Pedrazzini,et al.  Dilated cardiomyopathy and impaired cardiac hypertrophic response to angiotensin II in mice lacking FGF-2. , 2001, The Journal of clinical investigation.

[21]  Marco Presta,et al.  Paracrine and autocrine effects of fibroblast growth factor-4 in endothelial cells , 2001, Oncogene.

[22]  L. Claesson‐Welsh,et al.  FGF and VEGF function in angiogenesis: signalling pathways, biological responses and therapeutic inhibition. , 2001, Trends in pharmacological sciences.

[23]  R. Fandrich,et al.  Overexpression of FGF-2 increases cardiac myocyte viability after injury in isolated mouse hearts. , 2001, American journal of physiology. Heart and circulatory physiology.

[24]  R. Hammer,et al.  Tie2-Cre transgenic mice: a new model for endothelial cell-lineage analysis in vivo. , 2001, Developmental biology.

[25]  P. Claus,et al.  Molecular cloning and developmental expression of rat fibroblast growth factor receptor 3 , 2001, Histochemistry and Cell Biology.

[26]  Jian Li,et al.  Basic FGF reduces stunning via a NOS2-dependent pathway in coronary-perfused mouse hearts. , 2000, American journal of physiology. Heart and circulatory physiology.

[27]  S. Pawlowski,et al.  Fibroblast growth factor-2 mediates pressure-induced hypertrophic response. , 1999, The Journal of clinical investigation.

[28]  P. Dell’Era,et al.  Basic fibroblast growth factor-induced angiogenic phenotype in mouse endothelium. A study of aortic and microvascular endothelial cell lines. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[29]  K. Groebe,et al.  Calibration of misonidazole labeling by simultaneous measurement of oxygen tension and labeling density in multicellular spheroids , 1995, International journal of cancer.

[30]  P. Cuevas,et al.  Protection of rat myocardium by mitogenic and non-mitogenic fibroblast growth factor during post-ischemic reperfusion. , 1997, Growth factors.