Endothelium-targeted overexpression of constitutively active FGF receptor induces  cardioprotection in mice myocardial infarction.
Fibroblast growth factor receptor (FGFR) is expressed in a variety of cells and is involved in their proliferation/migration/survival. To elucidate FGFR-mediated specific action of vascular endothelial cells (ECs) on myocardial ischemia, we generated endothelium-targeted transgenic mice overexpressing constitutively active FGFR2 using Tie2 promoter (FGFR2-Tg). Infarct size, vessel formation and blood perfusion were significantly improved 28 days after myocardial infarction (MI) in FGFR2-Tg, compared with wild-type mice. Aortic ECs isolated from FGFR-Tg showed a marked increase in migratory capacity and tube formation. These in vitro angiogenic activities were blocked by PI3-kinase inhibitor. Whereas, parameters obtained from echocardiography were already improved at three days after MI. Cardiomyocyte apoptosis at the ischemic border zone was decreased in FGFR2-Tg (32.1%, p < 0.05) and cardiac mRNA expression of FGF2 (basic FGF) was also up-regulated (142%, p < 0.05) at 3 days after MI. 1% oxygen-mediated apoptosis was significantly inhibited in FGFR2-Tg-ECs and this inhibition was abolished by PI3-kinase inhibitor. FGFR2-Tg-ECs exposed to 1% oxygen exhibited enhanced phosphorylation of 416-Tyr-Src, 473-Ser-Akt, and HIF1alpha accumulation. The production of FGF2 was enhanced 2.1-fold in FGFR-Tg-ECs under 1% oxygen via the Src/Akt/HIF1alpha pathway, which induced the peri-vessel migration of vascular smooth muscle cells (VSMCs) and anti-apoptotic effects on VSMCs and cardiomyocytes. FGF receptor signaling in ECs promoted migration, survival and autocrine production of FGF2, leading to reduced infarct size, which is associated with anti-apoptotic action in the early stage and with enhanced angiogenesis in the late stage after MI.
Matsunaga
Shinsaku
S
Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan.
Okigaki
Mitsuhiko
M
Takeda
Mitsuo
M
Matsui
Akihiro
A
Honsho
Shoken
S
Katsume
Asako
A
Kishita
Eigo
E
Che
Jishan
J
Jishan
Che
C
Kurihara
Tatsuya
T
Adachi
Yasushi
Y
Mansukhani
Alka
A
Kobara
Miyuki
M
Matoba
Satoaki
S
Matoba
Yoshiaki
Y
Tatsumi
Tetsuya
T
Matsubara
Hiroaki
H
D000818:Animals; D017209:Apoptosis; D019898:Autocrine Communication; D002465:Cell Movement; D042783:Endothelial Cells / Q000201:enzymology / Q000473:pathology; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000473:pathology; D004789:Enzyme Activation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D009203:Myocardial Infarction / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D018919:Neovascularization, Physiologic; D009928:Organ Specificity; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism*; D042787:Receptor, TIE-2 / Q000235:genetics; D019061:src-Family Kinases / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019869:Phosphatidylinositol 3-Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2; D042787:Receptor, TIE-2; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt