FOXO1-mediated activation of Akt plays a critical role in vascular homeostasis

Circ Res. 2014 Jul 7;115(2):238-251. doi: 10.1161/CIRCRESAHA.115.303227. Epub 2014 May 29.

Abstract

Rationale: 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.

Methods and 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.

Keywords: FoxO1 protein, human; angiogenesis; endothelial cells; mice, transgenic; transcription factors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Endothelial Cells / metabolism*
  • Enzyme Induction
  • Forkhead Box Protein O1
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / antagonists & inhibitors
  • Forkhead Transcription Factors / deficiency
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / physiology*
  • Heart Failure / genetics*
  • Heart Failure / physiopathology
  • Homeostasis
  • Human Umbilical Vein Endothelial Cells
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Multiprotein Complexes / physiology*
  • Neovascularization, Physiologic / genetics
  • Neovascularization, Physiologic / physiology*
  • Nitric Oxide Synthase Type III / biosynthesis
  • Nitric Oxide Synthase Type III / genetics
  • Organ Specificity
  • Proto-Oncogene Proteins c-akt / physiology*
  • RNA, Small Interfering / pharmacology
  • Recombinant Fusion Proteins
  • Signal Transduction / physiology
  • TOR Serine-Threonine Kinases / physiology*
  • Yolk Sac / blood supply

Substances

  • FOXO1 protein, human
  • FOXO3 protein, human
  • Forkhead Box Protein O1
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • Multiprotein Complexes
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III
  • TOR Serine-Threonine Kinases
  • Akt1 protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt