<i>FoxO1</i> is required in endothelial but not myocardial cell lineages during cardiovascular development

Sengupta, Arunima; Chakraborty, Santanu; Paik, Jihye; Yutzey, Katherine E.; Evans-Anderson, Heather J.

doi:10.1002/dvdy.23759

Cited by 32 publications

(24 citation statements)

References 34 publications

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“…However, another study reported that endothelial-specific deletion of FoxO1 is embryonic lethal 16 . Conditional deletion of all three FoxO factors in the endothelium is compatible with survival and protects against atherosclerosis in low-density lipoprotein receptor knockout mice 17 .…”

Section: Introductionmentioning

confidence: 99%

FOXO1-Mediated Activation of Akt Plays a Critical Role in Vascular Homeostasis

Dharaneeswaran

Abid

Yuan

et al. 2014

Circulation Research

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Rationale Forkhead box-O transcription factors (FoxOs) transduce a wide range of extracellular signals, resulting in changes in cell survival, cell cycle progression, and a number of cell type-specific responses. FoxO1 is expressed in many cell types, including endothelial cells. Previous studies have shown that FoxO1 knockout in mice results in embryonic lethality at E11 due to impaired vascular development. In contrast, somatic deletion of FoxO1 is associated with hyperproliferation of endothelial cells. 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 endothelial cell (EC)-specific disruption of FoxO1 in mice phenocopies the full knockout. While endothelial expression of FoxO1 rescued otherwise FoxO-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 VEGF-induced Akt-mTOR1 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.

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Section: Introductionmentioning

confidence: 99%

FOXO1-Mediated Activation of Akt Plays a Critical Role in Vascular Homeostasis

Dharaneeswaran

Abid

Yuan

et al. 2014

Circulation Research

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“…37 Endothelial-specific FoxO1 knockout showed defective vasculature remodeling and lethality at E10.5, suggesting that endothelial FoxO1 is essential to cardiovascular development. 41 Interestingly, FoxO3, another member of the FoxO family, was reported to regulate neuronal differentiation. In adult neural precursor cells, ASCL1, a proneuronal bHLH transcription factor, shares common targets with FoxO3 and FoxO3 could inhibit ASCL1-dependent transcription of neurogenic genes.…”

Section: Discussionmentioning

confidence: 99%

Functional regulation of FoxO1 in neural stem cell differentiation

et al. 2015

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Forkhead transcription factor family O (FoxO) maintains adult stem cell reserves by supporting their long-term proliferative potential. MicroRNAs (miRs) regulate neuronal stem/progenitor cell (NSPC) proliferation and differentiation during neural development by controlling the expression of a specific set of target genes. In the neurogenic subventricular zone, FoxO1 is specifically expressed in NSPCs and is no longer detected during the transition to neuroblast stage, forming an inverse correlation with miR-9 expression. The 3′-untranslated region of FoxO1 contains a conserved target sequence of miR-9 and FoxO1 expression is coordinated in concert with miR-9 during neuronal differentiation. Our study demonstrates that FoxO1 contributes to NSPC fate decision through its cooperation with the Notch signaling pathway.

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“…In rodents, Foxo1 activation following IRS2 deficiency, in the brain enhanced longevity, but promoted obesity and diabetes (Taguchi, et al 2007). Also, Foxo1 activation enhances myocardial survival upon induction of oxidative stress (Sengupta, et al 2012; Sengupta, et al 2011; Sengupta, et al 2009), and autophagy, for control of cell size following serum starvation (Sengupta et al 2009). Mice lacking systemic Foxo1 are embryonic lethal, since Foxo1 is required for endothelial cell lineage during cardiovascular development (Hosaka et al 2004; Sengupta et al 2012).…”

Section: Part 2: Mechanisms For Insulin Resistancementioning

confidence: 99%

“…Also, Foxo1 activation enhances myocardial survival upon induction of oxidative stress (Sengupta, et al 2012; Sengupta, et al 2011; Sengupta, et al 2009), and autophagy, for control of cell size following serum starvation (Sengupta et al 2009). Mice lacking systemic Foxo1 are embryonic lethal, since Foxo1 is required for endothelial cell lineage during cardiovascular development (Hosaka et al 2004; Sengupta et al 2012). In C. elegans , the Foxo1 ortholog Daf-16 enhances longevity when insulin/IGF-1 receptor signaling is inactivated, and potentially increases expression of anti-oxidative genes (MnSOD), and also stimulates lipid droplet accumulation (Ogg, et al 1997).…”

Section: Part 2: Mechanisms For Insulin Resistancementioning

confidence: 99%

Insulin signaling, resistance, and metabolic syndrome: insights from mouse models into disease mechanisms

Guo

2013

Journal of Endocrinology

474

455

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Insulin resistance is a major underlying mechanism for the “metabolic syndrome”, which is also known as insulin resistance syndrome. Metabolic syndrome is increasing at an alarming rate, becoming a major public and clinical problem worldwide. Metabolic syndrome is represented by a group of interrelated disorders, including obesity, hyperglycemia, hyperlipidemia, and hypertension. It is also a significant risk factor for cardiovascular disease and increased morbidity and mortality. Animal studies demonstrate that insulin and its signaling cascade normally control cell growth, metabolism and survival through activation of mitogen-activated protein kinases (MAPKs) and phosphotidylinositide-3-kinase (PI3K), of which activation of PI-3K-associated with insulin receptor substrate-1 and -2 (IRS1, 2) and subsequent Akt→Foxo1 phosphorylation cascade has a central role in control of nutrient homeostasis and organ survival. Inactivation of Akt and activation of Foxo1, through suppression IRS1 and IRS2 in different organs following hyperinsulinemia, metabolic inflammation, and over nutrition may provide the underlying mechanisms for metabolic syndrome in humans. Targeting the IRS→Akt→Foxo1 signaling cascade will likely provide a strategy for therapeutic intervention in the treatment of type 2 diabetes and its complications. This review discusses the basis of insulin signaling, insulin resistance in different mouse models, and how a deficiency of insulin signaling components in different organs contributes to the feature of the metabolic syndrome. Emphasis will be placed on the role of IRS1, IRS2, and associated signaling pathways that couple to Akt and the forkhead/winged helix transcription factor Foxo1.

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FoxO1 is required in endothelial but not myocardial cell lineages during cardiovascular development

Cited by 32 publications

References 34 publications

FOXO1-Mediated Activation of Akt Plays a Critical Role in Vascular Homeostasis

FOXO1-Mediated Activation of Akt Plays a Critical Role in Vascular Homeostasis

Functional regulation of FoxO1 in neural stem cell differentiation

Insulin signaling, resistance, and metabolic syndrome: insights from mouse models into disease mechanisms

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