A MST1–FOXO1 cascade establishes endothelial tip cell polarity and facilitates sprouting angiogenesis

Kim, Yoo Hyung; Choi, Jeongwoon; Yang, Myung Jin; Hong, Seon Pyo; Lee, Choong-kun; Kubota, Yoshiaki; Lim, Dae Sik; Koh, Gou Young

doi:10.1038/s41467-019-08773-2

Cited by 74 publications

(67 citation statements)

References 65 publications

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“…In particular, recent evidence suggests that hypoxiainduced reactive oxygen species (ROS) biosynthesis from mitochondria could be a major upstream regulator of Stk4 activation in endothelial cells. Activated stk4 promotes planar and perpendicular vascular branching for regulating tip endothelial cells polarity and sprouting angiogenesis (Kim et al, 2019). Moreover, it was recently shown that STK4 acts as pro-apoptotic factor in damaged venous endothelial cells by the MIEF1 pathway.…”

Section: Discussionmentioning

confidence: 99%

High-Throughput Sequencing to Detect Novel Likely Gene-Disrupting Variants in Pathogenesis of Sporadic Brain Arteriovenous Malformations

et al. 2020

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Molecular signaling that leads to brain arteriovenous malformation (bAVM) is to date elusive and this is firstly due to the low frequency of familial cases. Conversely, sporadic bAVM is the most diffuse condition and represents the main source to characterize the genetic basis of the disease. Several studies were conducted in order to detect both germ-line and somatic mutations linked to bAVM development and, in this context, next generation sequencing technologies offer a pivotal resource for the amount of outputted information. We performed whole exome sequencing on a young boy affected by sporadic bAVM. Paired-end sequencing was conducted on an Illumina platform and filtered variants were validated by Sanger sequencing. We detected 20 likely gene-disrupting variants affecting as many loci. Of these variants, 11 are inherited novel variants and one is a de novo nonsense variant, affecting STK4 gene. Moreover, we also considered rare known variants affecting loci involved in vascular differentiation. In order to explain their possible involvement in bAVM pathogenesis, we analyzed molecular networks at Cytoscape platform. In this study we focus on some genetic point variations detected in a child affected by bAVM. Therefore, we suggest these novel affected loci as prioritized for further investigation on pathogenesis of bAVM lesions.

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Section: Discussionmentioning

confidence: 99%

High-Throughput Sequencing to Detect Novel Likely Gene-Disrupting Variants in Pathogenesis of Sporadic Brain Arteriovenous Malformations

et al. 2020

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“…The knock-down of Nucleolin in HUVECs lead to disorientation of the actin cytoskeleton inducing a loss of cell polarization as indicated by a change in cell shape towards a less elongated phenotype. Recent evidence suggests that MST1–FOXO1-mediated endothelial tip cell polarity facilitates sprouting angiogenesis 95 . MST1-FOXO1 was shown to be essential for directional migration of tip cells towards hypoxic regions and endothelial-specific deletion of either MST1 or FOXO1 lead to loss of endothelial tip cell polarity resulting in impaired sprouting angiogenesis 95 .…”

Section: Discussionmentioning

confidence: 99%

“…Recent evidence suggests that MST1–FOXO1-mediated endothelial tip cell polarity facilitates sprouting angiogenesis 95 . MST1-FOXO1 was shown to be essential for directional migration of tip cells towards hypoxic regions and endothelial-specific deletion of either MST1 or FOXO1 lead to loss of endothelial tip cell polarity resulting in impaired sprouting angiogenesis 95 . Indeed, in our bulk RNA sequencing data, we found a downregulation of FOXO1 upon Nucleolin knock-down, indicating a regulatory role for Nucleolin on MST1-FOXO1-mediated regulation of cell polarity.…”

Section: Discussionmentioning

confidence: 99%

Nucleolin is expressed in human fetal brain development and reactivated in human glial brain tumors regulating angiogenesis and vascular metabolism

Trizio

Shiu

Ghobrial

et al. 2020

Preprint

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Glioblastoma (GBM) is amongst the deadliest human cancers and is characterized by high levels of vascularisation. Angiogenesis is highly dynamic during brain development and almost quiescent in the adult brain, but is reactivated in vascular-dependent CNS pathologies such as brain tumors. Nucleolin (NCL) is a known regulator of cell proliferation and angiogenesis, but its roles on physiological and pathological brain vasculature remain unknown. Here, we studied the expression of Nucleolin in the neurovascular unit (NVU) in human fetal brains and human gliomas in vivo as well as its effects on sprouting angiogenesis and endothelial metabolism in vitro. Nucleolin is highly expressed in endothelial- and perivascular cells during brain development, downregulated in the adult brain, and upregulated in glioma. Moreover, Nucleolin expression in tumor- and blood vessel cells correlated with glioma malignancy in vivo. In culture, siRNA-mediated NCL knockdown reduced human umbilical vein endothelial cell (HUVEC) sprouting angiogenesis, proliferation and filopodia extension, and reduced glucose metabolism. Mechanistically, RNA sequencing of Nucleolin knockdown in HUVECs revealed a putative p53-TIGAR-HK2 regulation of endothelial glycolysis. These findings identify Nucleolin as a neurodevelopmental factor reactivated in glioma that positively regulates sprouting angiogenesis and endothelial metabolism. Our findings have important implications in therapeutic targeting of glioma.

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“…Nuclear FOXO1 will, in turn, activate the transcription of genes involved in the regulation of cell polarity and directional migration of tip cells toward hypoxic regions (Fig. 1) (94). Curiously, FOXO1 has been previously associated with the regulation of EC metabolism and quiescence (95).…”

Section: Dynamics Of Blood Vessel Formationmentioning

confidence: 99%

Endothelial cells on the move: dynamics in vascular morphogenesis and disease

2020

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The vascular system is a hierarchically organized network of blood vessels that play crucial roles in embryogenesis, homeostasis and disease. Blood vessels are built by endothelial cells - the cells lining the interior of blood vessels, through a process named vascular morphogenesis. Endothelial cells react to different biomechanical signals in their environment by adjusting their behavior: a) invade, proliferate and fuse to form new vessels (angiogenesis); b) remodel, regress and establish hierarchy in the network (patterning); c) maintain network stability (quiescence). Each step involves the coordination of endothelial cell differentiation, proliferation, polarity, migration, rearrangements and shape changes to ensure network integrity and an efficient barrier between blood and tissues. In this review, we highlighted the relevance and the mechanisms involving endothelial cell migration during different steps of vascular morphogenesis. We further present evidence on how impaired endothelial cell dynamics can contribute to pathology.

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A MST1–FOXO1 cascade establishes endothelial tip cell polarity and facilitates sprouting angiogenesis

Cited by 74 publications

References 65 publications

High-Throughput Sequencing to Detect Novel Likely Gene-Disrupting Variants in Pathogenesis of Sporadic Brain Arteriovenous Malformations

High-Throughput Sequencing to Detect Novel Likely Gene-Disrupting Variants in Pathogenesis of Sporadic Brain Arteriovenous Malformations

Nucleolin is expressed in human fetal brain development and reactivated in human glial brain tumors regulating angiogenesis and vascular metabolism

Endothelial cells on the move: dynamics in vascular morphogenesis and disease

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