VEGF-C regulates lymphangiogenesis and capillary stability by regulation of PDGF-B

Mitsuho Onimaru, Yoshikazu Yonemitsu, Takaaki Fujii, Mitsugu Tanii, Toshiaki Nakano, Kazunori Nakagawa, Ri Ichiro Kohno, Mamoru Hasegawa, Shin Ichi Nishikawa, Katsuo Sueishi

Research output: Contribution to journalArticle

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Abstract

Emerging evidence indicates that the tight communication between vascular endothelial cells and mural cells using platelet-derived growth factor (PDGF)-BB is essential for capillary stabilization during the angiogenic process. However, little is known about the related regulator that determines PDGF-BB expression. Using murine models of therapeutic neovascularization, we here show that a typical lymphangiogenic factor, vascular endothelial growth factor (VEGF)-C, is an essential regulator determining PDGF-BB expression for vascular stabilization via a paracrine mode of action. The blockade of VEGF type 3 receptor (VEGFR3) using neutralizing antibody AFL-4 abrogated FGF-2-mediated limb salvage and blood flow recovery in severely ischemic hindlimb. Interestingly, inhibition of VEGFR3 activity not only diminished lymphangiogenesis, but induced marked dilatation of capillary vessels, showing mural cell dissociation. In these mice, VEGF-C and PDGF-B were upregulated in the later phase after induced ischemia, on day 7, when exogenous FGF-2 expression had already declined, and blockade of VEGFR3 or PDGF-BB activities diminished PDGF-B or VEGF-C expression, respectively. These results clearly indicate that VEGF-C is a critical mediator, not only for lymphangiogenesis, but also for capillary stabilization, the essential molecular mechanism of communication between endothelial cells and mural cells during neovascularization.

Original languageEnglish
Pages (from-to)H1685-H1696
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume297
Issue number5
DOIs
Publication statusPublished - Nov 1 2009

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Proto-Oncogene Proteins c-sis
Lymphangiogenesis
Vascular Endothelial Growth Factor C
Fibroblast Growth Factor 2
Endothelial Cells
Vascular Endothelial Growth Factor Receptor-3
Limb Salvage
Hindlimb
Neutralizing Antibodies
Blood Vessels
Dilatation
Ischemia
platelet-derived growth factor BB

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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VEGF-C regulates lymphangiogenesis and capillary stability by regulation of PDGF-B. / Onimaru, Mitsuho; Yonemitsu, Yoshikazu; Fujii, Takaaki; Tanii, Mitsugu; Nakano, Toshiaki; Nakagawa, Kazunori; Kohno, Ri Ichiro; Hasegawa, Mamoru; Nishikawa, Shin Ichi; Sueishi, Katsuo.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 297, No. 5, 01.11.2009, p. H1685-H1696.

Research output: Contribution to journalArticle

Onimaru, Mitsuho ; Yonemitsu, Yoshikazu ; Fujii, Takaaki ; Tanii, Mitsugu ; Nakano, Toshiaki ; Nakagawa, Kazunori ; Kohno, Ri Ichiro ; Hasegawa, Mamoru ; Nishikawa, Shin Ichi ; Sueishi, Katsuo. / VEGF-C regulates lymphangiogenesis and capillary stability by regulation of PDGF-B. In: American Journal of Physiology - Heart and Circulatory Physiology. 2009 ; Vol. 297, No. 5. pp. H1685-H1696.
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