Loss of endothelial glucocorticoid receptor promotes angiogenesis via upregulation of Wnt/β-catenin pathway

Liu, Bing; Zhou, Han; Zhang, Tie-Ning; Gao, Xixiang; Tao, Bo; Xing, Hao; Zhuang, Zhenwu; Dardik, Alan; Kyriakides, Themis R.; Goodwin, Julie E.

doi:10.1007/s10456-021-09773-x

Cited by 23 publications

(18 citation statements)

References 43 publications

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“…Notably, many of the GRNs identified by SCENIC featured enriched DNA binding motifs and upregulated gene expression for transcription factors identified in our ATAC-seq and RNA-seq analysis, such as JUN, FOXF1, and LEF1 (Figure 4C). Interestingly, Nuclear Receptor Subfamily 3 group C member 1 (Nr3c1), which encodes a glucocorticoid receptor and is involved in the regulation of WNT/b-catenin pathway (Liu et al, 2021) and albumin D-binding protein (Dbp), a proline amino-acid-rich domain basic leucine zipper (PAR bZip) transcription factor involved in circadian rhythm control in the blood brain barrier (Franken et al, 2000;Pulido et al, 2020), also showed an increase in regulon activity (Supplemental Figure 8A-C).…”

Section: Identification Of Gene Regulatory Network Involved In Brain Endothelial Developmentmentioning

confidence: 99%

Defining the Transcriptional and Epigenetic Basis of Organotypic Endothelial Diversity in the Developing and Adult Mouse

Gutierrez

Hill

Largoza

et al. 2021

Preprint

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Significant phenotypic differences exist between the vascular endothelium of different organs, including cell-cell junctions, paracellular fluid transport, shape, and mural cell coverage. These organ-specific morphological features ultimately manifest as different functional capacities, as demonstrated by the dramatic differences in capillary permeability between the leaky vessels of the liver compared to the almost impermeable vasculature found in the brain. While these morphological and functional differences have been long appreciated, the molecular basis of endothelial organ specialization remains unclear. To determine the epigenetic and transcriptional mechanisms driving this functional heterogeneity, we profiled accessible chromatin, as well as gene expression, in six different organs, across three distinct time points, during murine development and in adulthood. After identifying both common, and organ-specific DNA motif usage and transcriptional signatures, we then focused our studies on the endothelium of the central nervous system. Using single cell RNA-seq, we identified key gene regulatory networks governing brain blood vessel maturation, including TCF/LEF and FOX transcription factors. Critically, these unique regulatory regions and gene expression signatures are evolutionarily conserved in humans. Collectively, this work provides a valuable resource for identifying the transcriptional regulators controlling organ-specific endothelial specialization and provides novel insight into the gene regulatory networks governing the maturation and maintenance of the cerebrovasculature.

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Section: Identification Of Gene Regulatory Network Involved In Brain Endothelial Developmentmentioning

confidence: 99%

Defining the Transcriptional and Epigenetic Basis of Organotypic Endothelial Diversity in the Developing and Adult Mouse

Gutierrez

Hill

Largoza

et al. 2021

Preprint

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“…Our study found that β-catenin pathway was dramatically activated in PF rats, treatment with 3-MA remarkably decreased the expression of β-catenin in fibrotic peritoneum. The activation of autophagy could augment the WNT/β-catenin signaling pathway ( Liu et al, 2021 ), as a result, β-catenin binds to the T cell factor/lymphoid enhancer-binding factor (TCL/LEF) family in the nucleus, and changes the expression of crucial mediators of angiogenesis, such as VEGF ( Liu et al, 2021 ). In addition, autophagy also regulates pigment epithelium derived factor (PEDF) expression, an endogenous VEGF inhibitor, and increases VEGF/PEDF ratio, promoting the formation of neovascularization ( Li et al, 2019b ).…”

Section: Discussionmentioning

confidence: 99%

Blockade of Autophagy Prevents the Development and Progression of Peritoneal Fibrosis

Shi

Wang

et al. 2021

Front. Pharmacol.

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Peritoneal fibrosis (PF) is a major cause of ultrafiltration failure in long-term peritoneal dialysis (PD) patients. Nevertheless, limited measures have been shown to be effective for the prevention and treatment of PF. Some views reveal that activation of autophagy ameliorates PF but others demonstrate that autophagy promotes PF. It is obvious that the role of autophagy in PF is controversial and further studies are needed. Here, we investigated the role of autophagy in rat models of PF and damaged cultured human peritoneal mesothelial cells (HPMCs). Autophagy was highly activated in fibrotic peritoneum from two PF rat models induced by 4.25% peritoneal dialysate fluid (PDF) and 0.1% chlorhexidine gluconate (CG). Blockade of autophagy with 3-MA effectively prevented PF in both models and reversed epithelial to mesenchymal transition (EMT) by down-regulating TGF-β/Smad3 signaling pathway and downstream nuclear transcription factors Slug and Snail. Treatment with 3-MA also inhibited activation of EGFR/ERK1/2 signaling pathway during PF. Moreover, 3-MA prominently decreased STAT3/NF-κB-mediated inflammatory response and macrophage infiltration, and prevented peritoneal angiogenesis through downregulation of β-catenin signal. In addition, TGF-β1 stimulation up-regulated autophagic activity as evidenced by the increased autophagosome in vitro. Exposure of HPMCs to TGF-β1 resulted in the induction of EMT and activation of TGF-β/Smad3, EGFR/ERK1/2 signaling pathways. Treatment with 3-MA blocked all these responses. In addition, delayed administration of 3-MA was effective in reducing EMT induced by TGF-β1. Taken together, our study indicated that autophagy might promote PF and 3-MA had anti-fibrosis effect in vivo and in vitro. These results suggest that autophagy could be a potential target on PF therapy for clinical patients with long-term PD.

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“… 90 Lack of endothelial the glucocorticoid receptor (GR) triggers autophagy flux, which will lead to activation of Wnt/β‐catenin signalling and promote angiogenesis. 91 In a muscle injury mouse model induced by hindlimb ischaemia, the autophagy pathway was induced under prolonged hypoxia in ECs, which could increase the angiogenic activities of ECs under tissue regeneration and consequently helps regeneration of surrounding tissues. 10 , 91 The transcription factor TFEB, demonstrated as a crucial regulator of lysosomal biogenesis and autophagy, 32 may mediate the link between endothelial autophagy and angiogenesis.…”

Section: Autophagy In Non‐myogenic Cellsmentioning

confidence: 99%

“… 91 In a muscle injury mouse model induced by hindlimb ischaemia, the autophagy pathway was induced under prolonged hypoxia in ECs, which could increase the angiogenic activities of ECs under tissue regeneration and consequently helps regeneration of surrounding tissues. 10 , 91 The transcription factor TFEB, demonstrated as a crucial regulator of lysosomal biogenesis and autophagy, 32 may mediate the link between endothelial autophagy and angiogenesis. Mechanistically, TFEB is up‐regulated in ischaemic skeletal muscle, subsequently activates AMPKα signalling and up‐regulates autophagy, which are essential for angiogenesis during skeletal muscle regeneration.…”

Section: Autophagy In Non‐myogenic Cellsmentioning

confidence: 99%

Autophagy in muscle regeneration: potential therapies for myopathies

Chen

Liu

et al. 2022

J cachexia sarcopenia muscle

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Autophagy classically functions as a physiological process to degrade cytoplasmic components, protein aggregates, and/or organelles, as a mechanism for nutrient breakdown, and as a regulator of cellular architecture. Its biological functions include metabolic stress adaptation, stem cell differentiation, immunomodulation and diseases regulation, and so on. Current researches have proved that autophagy dysfunction may contribute to the pathogenesis of some myopathies through impairment of myofibres regeneration. Studies of autophagy inhibition also indicate the importance of autophagy in muscle regeneration, while activation of autophagy can restore muscle function in some myopathies. In this review, we aim to report the mechanisms of action of autophagy on muscle regeneration to provide relevant references for the treatment of regenerating defective myopathies by regulating autophagy. Results have shown that one key mechanism of autophagy regulating the muscle regeneration is to affect the differentiation fate of muscle stem cells (MuSCs), including quiescence maintenance, activation and differentiation. The roles of autophagy (organelle/protein degradation, energy facilitation, and/or other) vary at different myogenic stages of the repair process. When the muscle is in homeostasis, basal autophagy can maintain the quiescence state and stemness of MuSCs by renewing organelle and protein. After injury, the increased autophagy flux contributes to meet biological energy demand of MuSCs during activation and proliferation. By mitochondrial remodelling, autophagy during differentiation can promote the metabolic transformation and balance mitochondrial‐mediated apoptosis signals in myoblasts. Autophagy in mature myofibres is also essential for the degradation of necrotic myofibres, and may affect the dynamics of MuSCs by affecting the secretion spectrum of myofibres or the recruitment of supporting cells. Except for myogenic cells, autophagy also plays an important role in regulating the function of non‐myogenic cells in the muscle microenvironment, which is also essential for successful muscle recovery. Autophagy can regulate the immune microenvironment during muscle regeneration through the recruitment and polarization of macrophages, while autophagy in endothelial cells can regulate muscle regeneration in an angiogenic or angiogenesis‐independent manner. Drug or nutrition targeted autophagy has been preliminarily proved to restore muscle function in myopathies by promoting muscle regeneration, and further understanding the role and mechanism of autophagy in various cell types during muscle regeneration will enable more effective combinatorial therapeutic strategies.

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Loss of endothelial glucocorticoid receptor promotes angiogenesis via upregulation of Wnt/β-catenin pathway

Cited by 23 publications

References 43 publications

Defining the Transcriptional and Epigenetic Basis of Organotypic Endothelial Diversity in the Developing and Adult Mouse

Defining the Transcriptional and Epigenetic Basis of Organotypic Endothelial Diversity in the Developing and Adult Mouse

Blockade of Autophagy Prevents the Development and Progression of Peritoneal Fibrosis

Autophagy in muscle regeneration: potential therapies for myopathies

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