title: The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis.
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. Tie2CrePten(flox/+) mice displayed enhanced tumorigenesis due to an increase in angiogenesis driven by vascular growth factors. This effect was partially dependent on the PI3K subunits p85alpha and p110gamma. In vitro, Tie2CrePten(flox/+) endothelial cells showed enhanced proliferation/migration. Tie2CrePten(flox/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 p110gamma rather than on p85alpha 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.
authors.affiliation: Department of Molecular Biology, Department of Microbiology, Department of Gastroenterology, Akita University School of Medicine, Akita 010-8543, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Hamada
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasaki
authors.forename: Pandelakis A
authors.initials: PA
authors.lastname: Koni
authors.forename: Miyuki
authors.initials: M
authors.lastname: Natsui
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kishimoto
authors.forename: Junko
authors.initials: J
authors.lastname: Sasaki
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yajima
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Horie
authors.forename: Go
authors.initials: G
authors.lastname: Hasegawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Naito
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Miyazaki
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
authors.forename: Tak Wah
authors.initials: TW
authors.lastname: Mak
authors.forename: Toru
authors.initials: T
authors.lastname: Nakano
authors.forename: Akira
authors.initials: A
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D005260:Female; D005318:Fetal Heart / Q000196:embryology / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009154:Mutation; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000235:genetics; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D019869:Phosphatidylinositol 3-Kinases; D017027:Protein Tyrosine Phosphatases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse