Distinct expression patterns of Flk1 and Flt1 in the coronary vascular system during development and after myocardial infarction

Shota Kurotsu, Rina Osakabe, Mari Isomi, Fumiya Tamura, Taketaro Sadahiro, Naoto Muraoka, Hidenori Kojima, Sho Haginiwa, Hidenori Tani, Kaori Nara, Yoshiaki Kubota, Masatsugu Ema, Keiichi Fukuda, Takeshi Suzuki, Masaki Ieda

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

The coronary vascular system is critical for myocardial growth and cardiomyocyte survival. However, the molecular mechanism regulating coronary angiogenesis remains elusive. Vascular endothelial growth factor (VEGF) regulates angiogenesis by binding to the specific receptors Flk1 and Flt1, which results in different functions. Despite the importance of Flk1 and Flt1, their expression in the coronary vasculature remains largely unknown due to the lack of appropriate antibodies for immunostaining. Here, we analyzed multiple reporter mice including Flk1-GFP BAC transgenic (Tg), Flk1-LacZ knock-in, Flt1-DsRed BAC Tg, and Flk1-GFP/Flt1-DsRed double Tg animals to determine expression patterns in mouse hearts during cardiac growth and after myocardial infarction (MI). We found that Flk1 was expressed in endothelial cells (ECs) with a pattern of epicardial-to-endocardial transmural gradients in the neonatal mouse ventricle, which was downregulated in adult coronary vessels with development. In contrast, Flt1 was homogeneously expressed in the ECs of neonatal mouse hearts and expression was maintained until adulthood. After MI, expression of both Flk1 and Flt1 was induced in the regenerating coronary vessels at day 7. Intriguingly, Flk1 expression was downregulated thereafter, whereas Flt1 expression was maintained in the newly formed coronary vessels until 30 days post-MI, recapitulating their expression kinetics during development. This is the first report demonstrating the spatiotemporal expression patterns of Flk1 and Flt1 in the coronary vascular system during development and after MI; thus, this study suggests that these factors have distinct and important functions in coronary angiogenesis.

Original languageEnglish
JournalBiochemical and Biophysical Research Communications
DOIs
Publication statusAccepted/In press - 2017 Jan 1

Fingerprint

Endothelial cells
Blood Vessels
Myocardial Infarction
Coronary Vessels
Vascular Endothelial Growth Factor A
Animals
Down-Regulation
Endothelial Cells
Genetically Modified Animals
Kinetics
Antibodies
Growth
Cardiac Myocytes
fluorescent protein 583

Keywords

  • Coronary vascular system
  • Endothelial cell
  • Flk1
  • Flt1
  • Myocardial infarction
  • VEGF

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Distinct expression patterns of Flk1 and Flt1 in the coronary vascular system during development and after myocardial infarction. / Kurotsu, Shota; Osakabe, Rina; Isomi, Mari; Tamura, Fumiya; Sadahiro, Taketaro; Muraoka, Naoto; Kojima, Hidenori; Haginiwa, Sho; Tani, Hidenori; Nara, Kaori; Kubota, Yoshiaki; Ema, Masatsugu; Fukuda, Keiichi; Suzuki, Takeshi; Ieda, Masaki.

In: Biochemical and Biophysical Research Communications, 01.01.2017.

Research output: Contribution to journalArticle

Kurotsu, Shota ; Osakabe, Rina ; Isomi, Mari ; Tamura, Fumiya ; Sadahiro, Taketaro ; Muraoka, Naoto ; Kojima, Hidenori ; Haginiwa, Sho ; Tani, Hidenori ; Nara, Kaori ; Kubota, Yoshiaki ; Ema, Masatsugu ; Fukuda, Keiichi ; Suzuki, Takeshi ; Ieda, Masaki. / Distinct expression patterns of Flk1 and Flt1 in the coronary vascular system during development and after myocardial infarction. In: Biochemical and Biophysical Research Communications. 2017.
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AU - Kurotsu, Shota

AU - Osakabe, Rina

AU - Isomi, Mari

AU - Tamura, Fumiya

AU - Sadahiro, Taketaro

AU - Muraoka, Naoto

AU - Kojima, Hidenori

AU - Haginiwa, Sho

AU - Tani, Hidenori

AU - Nara, Kaori

AU - Kubota, Yoshiaki

AU - Ema, Masatsugu

AU - Fukuda, Keiichi

AU - Suzuki, Takeshi

AU - Ieda, Masaki

PY - 2017/1/1

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N2 - The coronary vascular system is critical for myocardial growth and cardiomyocyte survival. However, the molecular mechanism regulating coronary angiogenesis remains elusive. Vascular endothelial growth factor (VEGF) regulates angiogenesis by binding to the specific receptors Flk1 and Flt1, which results in different functions. Despite the importance of Flk1 and Flt1, their expression in the coronary vasculature remains largely unknown due to the lack of appropriate antibodies for immunostaining. Here, we analyzed multiple reporter mice including Flk1-GFP BAC transgenic (Tg), Flk1-LacZ knock-in, Flt1-DsRed BAC Tg, and Flk1-GFP/Flt1-DsRed double Tg animals to determine expression patterns in mouse hearts during cardiac growth and after myocardial infarction (MI). We found that Flk1 was expressed in endothelial cells (ECs) with a pattern of epicardial-to-endocardial transmural gradients in the neonatal mouse ventricle, which was downregulated in adult coronary vessels with development. In contrast, Flt1 was homogeneously expressed in the ECs of neonatal mouse hearts and expression was maintained until adulthood. After MI, expression of both Flk1 and Flt1 was induced in the regenerating coronary vessels at day 7. Intriguingly, Flk1 expression was downregulated thereafter, whereas Flt1 expression was maintained in the newly formed coronary vessels until 30 days post-MI, recapitulating their expression kinetics during development. This is the first report demonstrating the spatiotemporal expression patterns of Flk1 and Flt1 in the coronary vascular system during development and after MI; thus, this study suggests that these factors have distinct and important functions in coronary angiogenesis.

AB - The coronary vascular system is critical for myocardial growth and cardiomyocyte survival. However, the molecular mechanism regulating coronary angiogenesis remains elusive. Vascular endothelial growth factor (VEGF) regulates angiogenesis by binding to the specific receptors Flk1 and Flt1, which results in different functions. Despite the importance of Flk1 and Flt1, their expression in the coronary vasculature remains largely unknown due to the lack of appropriate antibodies for immunostaining. Here, we analyzed multiple reporter mice including Flk1-GFP BAC transgenic (Tg), Flk1-LacZ knock-in, Flt1-DsRed BAC Tg, and Flk1-GFP/Flt1-DsRed double Tg animals to determine expression patterns in mouse hearts during cardiac growth and after myocardial infarction (MI). We found that Flk1 was expressed in endothelial cells (ECs) with a pattern of epicardial-to-endocardial transmural gradients in the neonatal mouse ventricle, which was downregulated in adult coronary vessels with development. In contrast, Flt1 was homogeneously expressed in the ECs of neonatal mouse hearts and expression was maintained until adulthood. After MI, expression of both Flk1 and Flt1 was induced in the regenerating coronary vessels at day 7. Intriguingly, Flk1 expression was downregulated thereafter, whereas Flt1 expression was maintained in the newly formed coronary vessels until 30 days post-MI, recapitulating their expression kinetics during development. This is the first report demonstrating the spatiotemporal expression patterns of Flk1 and Flt1 in the coronary vascular system during development and after MI; thus, this study suggests that these factors have distinct and important functions in coronary angiogenesis.

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KW - Endothelial cell

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KW - Flt1

KW - Myocardial infarction

KW - VEGF

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