Interplay of vascular endothelial growth factor receptors in organ-specific endothelial cell survival
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE185823 | GEO | 2022/01/01
REPOSITORIES: GEO
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Project description:Interplay of vascular endothelial growth factor receptors in organ-specific endothelial cell survival
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Project description:Chronic fibrosis is a hallmark of pathologic tissue remodelling that deteriorates organ function and eventually leads to death. Although fibroblasts are typically made responsible, it was recently suggested that endothelial cells contribute to fibrosis, although the functional importance of this phenomenon remained unclear. In this study, we addressed this question by genetic manipulation of the fibrogenic HMG-box transcription factor SOX9 specifically in vascular endothelial cells. Induced transgenic overexpression of SOX9 in these cells in mice triggered extensive fibrosis, organ growth and dysfunction in the heart, lung, liver and spleen. We found an upregulation of endogenous Sox9 in endothelial cells during cardiac, lung and liver fibrosis, and endothelial specific Sox9 deletion prevented fibrosis and organ dysfunction in mouse models of systolic and diastolic heart failure, as well as in mouse bleomycin induced pulmonary and non-alcoholic steato-hepatitis (NASH) triggered liver fibrosis. Mechanistically, a combined approach of bulk and single cell RNA sequencing of endothelial cells across multiple vascular beds revealed that Sox9 promoted the expression of extracellular matrix and matrix remodelling genes, growth factors, and inflammatory mediators, which triggered the expression of extracellular matrix directly by endothelial cells, but also activated fibroblasts. As we found the upregulation of endothelial Sox9 also in failing human hearts, we propose that endothelial Sox9 could be a target for anti-fibrotic therapy.
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Project description:Chronic fibrosis is a hallmark of pathologic tissue remodelling that deteriorates organ function and eventually leads to death. Although fibroblasts are typically made responsible, it was recently suggested that endothelial cells contribute to fibrosis, although the functional importance of this phenomenon remained unclear. In this study, we addressed this question by genetic manipulation of the fibrogenic HMG-box transcription factor SOX9 specifically in vascular endothelial cells. Induced transgenic overexpression of SOX9 in these cells in mice triggered extensive fibrosis, organ growth and dysfunction in the heart, lung, liver and spleen. We found an upregulation of endogenous Sox9 in endothelial cells during cardiac, lung and liver fibrosis, and endothelial specific Sox9 deletion prevented fibrosis and organ dysfunction in mouse models of systolic and diastolic heart failure, as well as in mouse bleomycin induced pulmonary and non-alcoholic steato-hepatitis (NASH) triggered liver fibrosis. Mechanistically, a combined approach of bulk and single cell RNA sequencing of endothelial cells across multiple vascular beds revealed that Sox9 promoted the expression of extracellular matrix and matrix remodelling genes, growth factors, and inflammatory mediators, which triggered the expression of extracellular matrix directly by endothelial cells, but also activated fibroblasts. As we found the upregulation of endothelial Sox9 also in failing human hearts, we propose that endothelial Sox9 could be a target for anti-fibrotic therapy.
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Project description:Chronic fibrosis is a hallmark of pathologic tissue remodelling that deteriorates organ function and eventually leads to death. Although fibroblasts are typically made responsible, it was recently suggested that endothelial cells contribute to fibrosis, although the functional importance of this phenomenon remained unclear. In this study, we addressed this question by genetic manipulation of the fibrogenic HMG-box transcription factor SOX9 specifically in vascular endothelial cells. Induced transgenic overexpression of SOX9 in these cells in mice triggered extensive fibrosis, organ growth and dysfunction in the heart, lung, liver and spleen. We found an upregulation of endogenous Sox9 in endothelial cells during cardiac, lung and liver fibrosis, and endothelial specific Sox9 deletion prevented fibrosis and organ dysfunction in mouse models of systolic and diastolic heart failure, as well as in mouse bleomycin induced pulmonary and non-alcoholic steato-hepatitis (NASH) triggered liver fibrosis. Mechanistically, a combined approach of bulk and single cell RNA sequencing of endothelial cells across multiple vascular beds revealed that Sox9 promoted the expression of extracellular matrix and matrix remodelling genes, growth factors, and inflammatory mediators, which triggered the expression of extracellular matrix directly by endothelial cells, but also activated fibroblasts. As we found the upregulation of endothelial Sox9 also in failing human hearts, we propose that endothelial Sox9 could be a target for anti-fibrotic therapy.
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Project description:Chronic fibrosis is a hallmark of pathologic tissue remodelling that deteriorates organ function and eventually leads to death. Although fibroblasts are typically made responsible, it was recently suggested that endothelial cells contribute to fibrosis, although the functional importance of this phenomenon remained unclear. In this study, we addressed this question by genetic manipulation of the fibrogenic HMG-box transcription factor SOX9 specifically in vascular endothelial cells. Induced transgenic overexpression of SOX9 in these cells in mice triggered extensive fibrosis, organ growth and dysfunction in the heart, lung, liver and spleen. We found an upregulation of endogenous Sox9 in endothelial cells during cardiac, lung and liver fibrosis, and endothelial specific Sox9 deletion prevented fibrosis and organ dysfunction in mouse models of systolic and diastolic heart failure, as well as in mouse bleomycin induced pulmonary and non-alcoholic steato-hepatitis (NASH) triggered liver fibrosis. Mechanistically, a combined approach of bulk and single cell RNA sequencing of endothelial cells across multiple vascular beds revealed that Sox9 promoted the expression of extracellular matrix and matrix remodelling genes, growth factors, and inflammatory mediators, which triggered the expression of extracellular matrix directly by endothelial cells, but also activated fibroblasts. As we found the upregulation of endothelial Sox9 also in failing human hearts, we propose that endothelial Sox9 could be a target for anti-fibrotic therapy.
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Project description:Chronic fibrosis is a hallmark of pathologic tissue remodelling that deteriorates organ function and eventually leads to death. Although fibroblasts are typically made responsible, it was recently suggested that endothelial cells contribute to fibrosis, although the functional importance of this phenomenon remained unclear. In this study, we addressed this question by genetic manipulation of the fibrogenic HMG-box transcription factor SOX9 specifically in vascular endothelial cells. Induced transgenic overexpression of SOX9 in these cells in mice triggered extensive fibrosis, organ growth and dysfunction in the heart, lung, liver and spleen. We found an upregulation of endogenous Sox9 in endothelial cells during cardiac, lung and liver fibrosis, and endothelial specific Sox9 deletion prevented fibrosis and organ dysfunction in mouse models of systolic and diastolic heart failure, as well as in mouse bleomycin induced pulmonary and non-alcoholic steato-hepatitis (NASH) triggered liver fibrosis. Mechanistically, a combined approach of bulk and single cell RNA sequencing of endothelial cells across multiple vascular beds revealed that Sox9 promoted the expression of extracellular matrix and matrix remodelling genes, growth factors, and inflammatory mediators, which triggered the expression of extracellular matrix directly by endothelial cells, but also activated fibroblasts. As we found the upregulation of endothelial Sox9 also in failing human hearts, we propose that endothelial Sox9 could be a target for anti-fibrotic therapy.
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Project description:GATA2 is well recognized as a key transcription factor and regulator of cell type specificity and differentiation. Here, we carried out comparative chromatin immunoprecipitation with comprehensive sequencing (ChIP-seq) to determine genome-wide occupancy of GATA2 in endothelial cells and erythroids, and compared the occupancy to the respective gene expression profile in each cell type. Although GATA2 was commonly expressed in both cell types, different GATA2 bindings and distinct cell specific gene expressions were observed. By using the ChIP-seq with epigenetic histone modifications and chromatin conformation capture assays; we elucidated the mechanistic regulation of endothelial-specific GATA2 mediated endomucin gene expression, that was regulated by the endothelial-specific chromatin loop with a GATA2 associated distal enhancer and core promoter. Knockdown of endomucin markedly attenuated endothelial cell growth, migration and tube formation. Moreover, abrogation of GATA2 in endothelium demonstrated not only a reduction of endothelial specific markers, but also induction of mesenchymal transition promoting gene expression. Our findings provide new insights into the correlation of endothelial expressed GATA2 binding, epigenetic modification, and the determination of endothelial cell specificity. Total 4 samples were derived from duplicate or triplicate arrays in HMVEC or K562 cells. Then, HMVEC were transfected with si-RNA against GATA2 in biological duplicate. Overall, 6 samples were uploaded.
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