The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis

Koichi Hamada, Takehiko Sasaki, Pandelakis A. Koni, Miyuki Natsui, Hiroyuki Kishimoto, Junko Sasaki, Nobuyuki Yajima, Yasuo Horie, Go Hasegawa, Makoto Naito, Jun Ichi Miyazaki, Toshio Suda, Hiroshi Itoh, Kazuwa Nakao, Wah Mak Tak, Toru Nakano, Akira Suzuki

Research output: Contribution to journalArticle

212 Scopus citations

Abstract

PTEN is an important tumor suppressor gene. Hereditary mutation of PTEN causes tumor-susceptibility diseases such as Cowden disease. We used the Cre-loxP system to generate an endothelial cell-specific mutation of Pten (Tie2CrePten) in mice. Tie2CrePtenflox/+ mice displayed enhanced tumorigenesis due to an increase in angiogenesis driven by vascular growth factors. This effect was partially dependent on the PI3K subunits p85α and p110γ. In vitro, Tie2CrePtenflox/+ endothelial cells showed enhanced proliferation/migration. Tie2CrePtenflox/flox mice died before embryonic day 11.5 (E11.5) due to bleeding and cardiac failure caused by impaired recruitment of pericytes and vascular smooth muscle cells to blood vessels, and of cardiomyocytes to the endocardium. These phenotypes depend strongly on p110γ rather than on p85α and were associated with decreased expression of Ang-1, VCAM-1, connexin 40, and ephrinB2 but increased expression of Ang-2, VEGF-A, VEGFR1, and VEGFR2. Pten is thus indispensable for normal cardiovascular morphogenesis and post-natal angiogenesis, including tumor angiogenesis.

Original languageEnglish (US)
Pages (from-to)2054-2065
Number of pages12
JournalGenes and Development
Volume19
Issue number17
DOIs
StatePublished - Sep 1 2005

Keywords

  • Cardiovasculogenesis
  • Endothelial cells
  • PI3K
  • PTEN
  • Tumor angiogenesis

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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    Hamada, K., Sasaki, T., Koni, P. A., Natsui, M., Kishimoto, H., Sasaki, J., Yajima, N., Horie, Y., Hasegawa, G., Naito, M., Miyazaki, J. I., Suda, T., Itoh, H., Nakao, K., Tak, W. M., Nakano, T., & Suzuki, A. (2005). The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis. Genes and Development, 19(17), 2054-2065. https://doi.org/10.1101/gad.1308805