FOXO1 stimulates tip cell-enriched gene expression in endothelial cells

Miyamura, Yuri; Kamei, Shunsuke; Matsuo, Misaki; Yamazaki, Masaya; Usuki, Shingo; Yasunaga, Keiichiro; Uemura, Akiyoshi; Satou, Yorifumi; Ohguchi, Hiroto; Minami, Takashi

doi:10.1016/j.isci.2024.109161

Cited by 3 publications

(5 citation statements)

References 49 publications

(76 reference statements)

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“…This observation aligns with the concept that tip ECs exhibit lower proliferation and reduced reliance on glycolysis compared with non-tip ECs (Table 4). Furthermore, after both FOXO1 knockdown and under hypoxic conditions, we observed a relative increase in the number of tip cells (Miyamura et al, 2024). This phenomenon may be explained by a reduced fraction of proliferating non-tip ECs which is in agreement with the recently published article by Miyamura et al 115 that reported that FOXO1 stimulates the tip ECs.…”

Section: Atp Synthesis In Tip and Non-tip Endothelial Cellssupporting

confidence: 91%

“…Furthermore, after both FOXO1 knockdown and under hypoxic conditions, we observed a relative increase in the number of tip cells (Miyamura et al, 2024). This phenomenon may be explained by a reduced fraction of proliferating non-tip ECs which is in agreement with the recently published article by Miyamura et al 115 that reported that FOXO1 stimulates the tip ECs. How tip ECs generate ATP needed for migration is not clear yet.…”

Section: Atp Synthesis In Tip and Non-tip Endothelial Cellssupporting

confidence: 91%

“…However, we hypothesize that FOXO1 expression is relatively less reduced in tip ECs compared with non-tip ECs. This hypothesis is supported by our finding that FOXO1 mRNA levels in tip ECs in vitro are higher than those in non-tip ECs (Miyamura et al, 2024). This observation aligns with the concept that tip ECs exhibit lower proliferation and reduced reliance on glycolysis compared with non-tip ECs (Table 4).…”

Section: Atp Synthesis In Tip and Non-tip Endothelial Cellssupporting

confidence: 88%

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New Insights in ATP Synthesis as Therapeutic Target in Cancer and Angiogenic Ocular Diseases

van Noorden,

Yetkin-Arik,

Serrano Martinez

et al. 2024

J Histochem Cytochem.

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Lactate and ATP formation by aerobic glycolysis, the Warburg effect, is considered a hallmark of cancer. During angiogenesis in non-cancerous tissue, proliferating stalk endothelial cells (ECs) also produce lactate and ATP by aerobic glycolysis. In fact, all proliferating cells, both non-cancer and cancer cells, need lactate for the biosynthesis of building blocks for cell growth and tissue expansion. Moreover, both non-proliferating cancer stem cells in tumors and leader tip ECs during angiogenesis rely on glycolysis for pyruvate production, which is used for ATP synthesis in mitochondria through oxidative phosphorylation (OXPHOS). Therefore, aerobic glycolysis is not a specific hallmark of cancer but rather a hallmark of proliferating cells and limits its utility in cancer therapy. However, local treatment of angiogenic eye conditions with inhibitors of glycolysis may be a safe therapeutic option that warrants experimental investigation. Most types of cells in the eye such as photoreceptors and pericytes use OXPHOS for ATP production, whereas proliferating angiogenic stalk ECs rely on glycolysis for lactate and ATP production. (J Histochem Cytochem XX.XXX–XXX, XXXX)

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Section: Atp Synthesis In Tip and Non-tip Endothelial Cellssupporting

confidence: 91%

Section: Atp Synthesis In Tip and Non-tip Endothelial Cellssupporting

confidence: 91%

Section: Atp Synthesis In Tip and Non-tip Endothelial Cellssupporting

confidence: 88%

See 1 more Smart Citation

New Insights in ATP Synthesis as Therapeutic Target in Cancer and Angiogenic Ocular Diseases

van Noorden,

Yetkin-Arik,

Serrano Martinez

et al. 2024

J Histochem Cytochem.

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“…To investigate this further we measured protein levels of ANG2 using ELISA and the results showed a slightly (statistically non-significant) higher expression levels of ANG2 in TIE2 L914F iECs. We subsequently investigated the localization of FOXO1, a known regulator of ANG2 expression [42,43] that is located to the cytosol upon phosphorylation induced by TIE2/AKT signaling [44]. Our observations revealed a significant reduction in FOXO1 localization within the nucleus in TIE2 L914F iECs, also indicating an active TIE2 pathway (Supp.…”

Section: Tie2 L914f Iecs Results In Gene Expression Profiles Implicat...mentioning

confidence: 85%

“…The regulation of ANG2 transcription by the FOXO1 transcription factor is well-established [42,43], and it is known that the TIE2 pathway can induce the phosphorylation of FOXO1, leading to its translocation from the nucleus to the cytosol and subsequent inactivation [44]. Consequently, differences in ANG2 expression observed between experimental conditions may be attributed to the overexpression of TIE2 L914F in the HUVEC model resulting in complete clearance of FOXO1 from the nucleus, indicative of its inactive state.…”

Section: Discussionmentioning

confidence: 99%

Human iPSC and CRISPR targeted gene knock-in strategy for studying the somatic TIE2L914F mutation in endothelial cells

Lazovic,

Nguyen,

Ansarizadeh

et al. 2024

Angiogenesis

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Induced pluripotent stem cell (iPSC) derived endothelial cells (iECs) have emerged as a promising tool for studying vascular biology and providing a platform for modelling various vascular diseases, including those with genetic origins. Currently, primary ECs are the main source for disease modelling in this field. However, they are difficult to edit and have a limited lifespan. To study the effects of targeted mutations on an endogenous level, we generated and characterized an iPSC derived model for venous malformations (VMs). CRISPR-Cas9 technology was used to generate a novel human iPSC line with an amino acid substitution L914F in the TIE2 receptor, known to cause VMs. This enabled us to study the differential effects of VM causative mutations in iECs in multiple in vitro models and assess their ability to form vessels in vivo. The analysis of TIE2 expression levels in TIE2L914F iECs showed a significantly lower expression of TIE2 on mRNA and protein level, which has not been observed before due to a lack of models with endogenous edited TIE2L914F and sparse patient data. Interestingly, the TIE2 pathway was still significantly upregulated and TIE2 showed high levels of phosphorylation. TIE2L914F iECs exhibited dysregulated angiogenesis markers and upregulated migration capability, while proliferation was not affected. Under shear stress TIE2L914F iECs showed reduced alignment in the flow direction and a larger cell area than TIE2WT iECs. In summary, we developed a novel TIE2L914F iPSC-derived iEC model and characterized it in multiple in vitro models. The model can be used in future work for drug screening for novel treatments for VMs.

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Macrophages play a crucial role in vascular smooth muscle cell coverage

Niimi,

Nakae,

Kubota

et al. 2024

Development

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The microvascular system consists of two cell types: endothelial and mural (pericytes and vascular smooth muscle cells; VSMCs) cells. Communication between endothelial and mural cells plays a pivotal role in the maintenance of vascular homeostasis; however, in vivo molecular and cellular mechanisms underlying mural cell development remain unclear. In this study, we found that macrophages played a crucial role in TGFβ-dependent pericyte-to-VSMC differentiation during retinal vasculature development. In mice with constitutively-active Foxo1-overexpression, substantial accumulation of TGFβ1-producing macrophages and pericytes around the angiogenic front region was observed. Additionally, the TGFβ-SMAD pathway was activated in pericytes adjacent to macrophages, resulting in an excess ectopic α-smooth muscle actin-positive VSMCs. Furthermore, we identified endothelial SEMA3C as an attractant for macrophages. In vivo neutralization of SEMA3C rescued macrophage accumulation and ectopic VSMC phenotypes in the mice, as well as drug-induced macrophage depletion. Therefore, macrophages play an important physiological role in VSMC development via the FOXO1-SEMA3C pathway.

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FOXO1 stimulates tip cell-enriched gene expression in endothelial cells

Cited by 3 publications

References 49 publications

New Insights in ATP Synthesis as Therapeutic Target in Cancer and Angiogenic Ocular Diseases

New Insights in ATP Synthesis as Therapeutic Target in Cancer and Angiogenic Ocular Diseases

Human iPSC and CRISPR targeted gene knock-in strategy for studying the somatic TIE2L914F mutation in endothelial cells

Macrophages play a crucial role in vascular smooth muscle cell coverage

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