title: Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin.
abstract: Endothelial cells in growing tumors express activated Akt, which when modeled by transgenic endothelial expression of myrAkt1 was sufficient to recapitulate the abnormal structural and functional features of tumor blood vessels in nontumor tissues. Sustained endothelial Akt activation caused increased blood vessel size and generalized edema from chronic vascular permeability, while acute permeability in response to VEGF-A was unaffected. These changes were reversible, demonstrating an ongoing requirement for Akt signaling for the maintenance of these phenotypes. Furthermore, rapamycin inhibited endothelial Akt signaling, vascular changes from myrAkt1, tumor growth, and tumor vascular permeability. Akt signaling in the tumor vascular stroma was sensitive to rapamycin, suggesting that rapamycin may affect tumor growth in part by acting as a vascular Akt inhibitor.
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Thuy L
authors.initials: TL
authors.lastname: Phung
authors.forename: Keren
authors.initials: K
authors.lastname: Ziv
authors.forename: Donnette
authors.initials: D
authors.lastname: Dabydeen
authors.forename: Godfred
authors.initials: G
authors.lastname: Eyiah-Mensah
authors.forename: Marcela
authors.initials: M
authors.lastname: Riveros
authors.forename: Carole
authors.initials: C
authors.lastname: Perruzzi
authors.forename: Jingfang
authors.initials: J
authors.lastname: Sun
authors.forename: Rita A
authors.initials: RA
authors.lastname: Monahan-Earley
authors.forename: Ichiro
authors.initials: I
authors.lastname: Shiojima
authors.forename: Janice A
authors.initials: JA
authors.lastname: Nagy
authors.forename: Michelle I
authors.initials: MI
authors.lastname: Lin
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.forename: Ann M
authors.initials: AM
authors.lastname: Dvorak
authors.forename: David M
authors.initials: DM
authors.lastname: Briscoe
authors.forename: Michal
authors.initials: M
authors.lastname: Neeman
authors.forename: William C
authors.initials: WC
authors.lastname: Sessa
authors.forename: Harold F
authors.initials: HF
authors.lastname: Dvorak
authors.forename: Laura E
authors.initials: LE
authors.lastname: Benjamin
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D002478:Cells, Cultured; D004487:Edema / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
chemical_list: D042461:Vascular Endothelial Growth Factor A; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus