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

H Dharaneeswaran, MR Abid, L Yuan… - Circulation …, 2014 - Am Heart Assoc
H Dharaneeswaran, MR Abid, L Yuan, D Dupuis, D Beeler, KC Spokes, L Janes, T Sciuto…
Circulation research, 2014Am Heart Assoc
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 …
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.
Am Heart Assoc