Cardiac-specific activation of signal transducer and activator of transcription 3 promotes vascular formation in the heart.
Signal transducer and activator of transcription 3 (STAT3) functions in cell proliferation, differentiation, and cell survival. Previously, we have demonstrated that the activation of STAT3 is required for glycoprotein 130-mediated induction of VEGF in cardiac myocytes, but the functional importance of STAT3 as an angiogenic mediator remains to be determined. To address this issue, we first generated the adenoviral vector expressing constitutively active STAT3 (caSTAT3). Adenoviral gene transfer of caSTAT3 induced an increase in the expression of VEGF in cultured cardiomyocytes. The conditioned medium from caSTAT3-transfected cardiomyocyte culture promoted endothelial tubule formation, which was inhibited by anti-VEGF antibody. Next, we generated the transgenic (TG) mice with cardiac-specific overexpression of caSTAT3 and demonstrated that caSTAT3 TG mice showed evidence of VEGF induction in the hearts. The caSTAT3 TG hearts also demonstrated increased capillary density accompanied by an increase in the expression of VE-cadherin, an endothelial-specific component. These data indicate that caSTAT3 TG hearts exhibit an enriched vascular structure compared with non-transgenic hearts. The study presented here provides the first evidence that activation of STAT3 controls vessel growth in vivo and suggests that STAT3 contributes to cardiac adaptation by regulating vascular function under the conditions of stress.
Osugi
Tomoaki
T
Department of Molecular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-oka Suita City, Osaka 565-0871, Japan.
Oshima
Yuichi
Y
Fujio
Yasushi
Y
Funamoto
Masanobu
M
Yamashita
Atsuko
A
Negoro
Shinji
S
Kunisada
Keita
K
Izumi
Masahiro
M
Nakaoka
Yoshikazu
Y
Hirota
Hisao
H
Okabe
Masaru
M
Yamauchi-Takihara
Keiko
K
Kawase
Ichiro
I
Kishimoto
Tadamitsu
T
D000209:Acute-Phase Proteins / Q000378:metabolism; D000256:Adenoviridae; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016228:Endothelial Growth Factors / Q000235:genetics; D005786:Gene Expression Regulation; D006321:Heart / Q000502:physiology*; D008222:Lymphokines / Q000235:genetics; D051379:Mice; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D018919:Neovascularization, Physiologic; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000209:Acute-Phase Proteins; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D008222:Lymphokines; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors