title: FOXO1-mediated activation of Akt plays a critical role in vascular homeostasis.
abstract: BACKGROUND
  Forkhead box-O transcription factors (FoxOs) transduce a wide range of extracellular signals, resulting in changes in cell survival, cell cycle progression, and several cell type-specific responses. FoxO1 is expressed in many cell types, including endothelial cells (ECs). Previous studies have shown that Foxo1 knockout in mice results in embryonic lethality at E11 because of impaired vascular development. In contrast, somatic deletion of Foxo1 is associated with hyperproliferation of ECs. Thus, the precise role of FoxO1 in the endothelium remains enigmatic.
  
  
  OBJECTIVE
  To determine the effect of endothelial-specific knockout and overexpression of FoxO1 on vascular homeostasis.
  
  
  RESULTS
  We show that EC-specific disruption of Foxo1 in mice phenocopies the full knockout. Although endothelial expression of FoxO1 rescued otherwise Foxo1-null animals, overexpression of constitutively active FoxO1 resulted in increased EC size, occlusion of capillaries, elevated peripheral resistance, heart failure, and death. Knockdown of FoxO1 in ECs resulted in marked inhibition of basal and vascular endothelial growth factor-induced Akt-mammalian target of rapamycin complex 1 (mTORC1) signaling.
  
  
  CONCLUSIONS
  Our findings suggest that in mice, endothelial expression of FoxO1 is both necessary and sufficient for embryonic development. Moreover, FoxO1-mediated feedback activation of Akt maintains growth factor responsive Akt/mTORC1 activity within a homeostatic range.
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston MA 02215.|Department of Medicine, Beth Israel Deaconess Medical Center, Boston MA 02215.
authors.forename: Harita
authors.initials: H
authors.lastname: Dharaneeswaran
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston MA 02215.|Department of Medicine, Beth Israel Deaconess Medical Center, Boston MA 02215.|Warren Alpert Medical School of Brown University, Cardiovascular Research Center, Rhode Island Hospital, Providence, RI 02903.
authors.forename: Md Ruhul
authors.initials: MR
authors.lastname: Abid
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston MA 02215.|Department of Medicine, Beth Israel Deaconess Medical Center, Boston MA 02215.
authors.forename: Lei
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston MA 02215.|Department of Medicine, Beth Israel Deaconess Medical Center, Boston MA 02215.
authors.forename: Dylan
authors.initials: D
authors.lastname: Dupuis
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston MA 02215.|Department of Medicine, Beth Israel Deaconess Medical Center, Boston MA 02215.
authors.forename: David
authors.initials: D
authors.lastname: Beeler
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston MA 02215.|Department of Medicine, Beth Israel Deaconess Medical Center, Boston MA 02215.
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Spokes
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston MA 02215.|Department of Medicine, Beth Israel Deaconess Medical Center, Boston MA 02215.
authors.forename: Lauren
authors.initials: L
authors.lastname: Janes
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston MA 02215.|Department of Pathology, Beth Israel Deaconess Medical Center, Boston MA 02215.
authors.forename: Tracey
authors.initials: T
authors.lastname: Sciuto
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Boston MA 02215.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kang
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston MA 02215.|Department of Pathology, Beth Israel Deaconess Medical Center, Boston MA 02215.
authors.forename: Shou-Ching S
authors.initials: SS
authors.lastname: Jaminet
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston MA 02215.|Department of Pathology, Beth Israel Deaconess Medical Center, Boston MA 02215.
authors.forename: Ann
authors.initials: A
authors.lastname: Dvorak
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston MA 02215.|Department of Medicine, Beth Israel Deaconess Medical Center, Boston MA 02215.
authors.forename: Marianne A
authors.initials: MA
authors.lastname: Grant
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston MA 02215.|Department of Medicine, Beth Israel Deaconess Medical Center, Boston MA 02215.
authors.forename: Erzsébet Ravasz
authors.initials: ER
authors.lastname: Regan
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston MA 02215.|Department of Medicine, Beth Israel Deaconess Medical Center, Boston MA 02215.
authors.forename: William C
authors.initials: WC
authors.lastname: Aird
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism*; D004790:Enzyme Induction; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006333:Heart Failure / Q000235:genetics* / Q000503:physiopathology; D006706:Homeostasis; D061307:Human Umbilical Vein Endothelial Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis / Q000235:genetics; D009928:Organ Specificity; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D015017:Yolk Sac / Q000098:blood supply
chemical_list: C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C514862:Akt1 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: FoxO1 protein, human; angiogenesis; endothelial cells; mice, transgenic; transcription factors