Abstract 438: Overexpression of Tie2-Promoted Activated Fibroblast Growth Factor Receptor 2 in Endothelial Cells Enhances Angiogenesis and Induces Cardioprotective Effect via Akt Signaling Pathway in Mice Myocardial Infarction
Introduction: Fibroblast growth factor (FGF) has been implicated in cell proliferation, migration, survival and differentiation via its tyrosine kinase receptors (FGFR). In hearts, FGF has been reported to confer protection from acute and chronic cardiac damage. However, the pathophysiological role of FGFR signaling in endothelial cells (ECs) for protecting the heart against ischemic injury has not been fully elucidated.
Methods and Results: Myocardial infarction (MI) was induced in transgenic mice overexpressing activated human FGFR2 linked to the Tie2 promoter (Tie2-FGFR-Tg) by ligating the left coronary artery. Infarct size (38.0% vs 47.4% in wild-type mice, p<0.05) and collagen accumulation quantitated by Masson’s Trichrome staining (8.1% vs 11.4% in wild-type mice, p<0.05) were significantly improved in Tie2-FGFR-Tg mice at 28 days after ligation. Echocardiographic parameters were also significantly improved at 3,7,14 and 28 days after ligation. The percentage of myocyte apoptosis in the ischemic border zone evaluated by TUNEL assay was significantly decreased in Tie2-FGFR-Tg mice (4.53% vs. 7.12% in wild-type mice, p<0.05). Although basal CD31+ capillary and αSMA+ arteriole numbers were not different between these mice, ischemia-induced capillarization and arteriogenesis was significantly increased in Tie2-FGFR-Tg mice. Real time PCR showed that basic FGF expression was increased at 3 days after ligation in Tie2-FGFR-Tg mice, compared with wild-type mice. Isolated ECs from the aorta of Tie2-FGFR-Tg mice showed a marked increase in VEGF-induced migratory capacity and tube formation by 1.88-fold and 2.04-fold, respectively, over wild-type mice. Moreover, serum-deprivation-induced ECs apoptosis was significantly inhibited in Tie2-FGFR-Tg mice. Western blot analysis showed that phosphorylation of Akt in ECs was significantly increased in Tie2-FGFR-Tg mice, and these in vitro angiogenic activities were significantly inhibited by phospho-inositide-3 kinase inhibitor.
Conclusion: The data suggest that activated FGFR signaling accelerates autocrine loop of FGF production and FGFR-mediated activation of Akt signaling plays an important role in mature neovascularization and cardioprotection after MI.