PI3K-mediated crosstalk between angiopoietin and vascular endothelial growth factor C signaling pathways is required for lymphangiogenesis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE202989 | GEO | 2022/06/29
REPOSITORIES: GEO
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Project description:Neural stem cells (NSCs) continuously produce new neurons within the adult mammalian hippocampus. However, this process declines with age and this decline correlates with defects in cognitive function and mood. Molecular mechanisms that activate quiescent NSCs to generate progenitor cells in vivo remain poorly understood. Here we show that adult hippocampal NSCs express VEGFR3, a key regulator of vascular and neural development, and are activated by the VEGFR3 ligand VEGF-C to enter the cell cycle and convert into progenitor cells. Conditional deletion of Vegfr3 in NSCs leads to a decline in hippocampal neurogenesis. Functionally, this is associated with increased anxiety behavior and compromised NSC activation in response to VEGF-C and physical activity. These findings establish VEGFR3 expression as a hallmark of adult mouse NSCs and demonstrate a specific requirement for VEGF-C/VEGFR signaling in NSC activation. Enhancing VEGFR3 signaling by VEGF-C may improve neurogenesis and mood during aging. Vegfr3 YFP and Vegfr3 YFP-negative cells were FACS-sorted from two separated groups of Vegfr3::YFP mice (16 mice/ each group; 12-30.10^5 Vegfr3YFP cells/group). Vegfr3 YFP and Vegfr3 YFP-negative cells were suspended in CCMM-BM- were seeded in 24-well plates with or without VEGF-C (50ng/ml). After an 18h-culture period,M-BM- the cells were collected in eppendorf tubes, washed in PBS, and the total RNAs were extracted by Qiagen RNA Micro kit (QIAGEN, Valencia, CA). For each culture condition, the pellets from the two groups of Vegfr3 YFP or Vegfr3 YFP-negative cells were pooled. The RNA integrity number (RIN) of each RNA sample was checked by 2100 Bioanalyzer of Agilent Technologies (Santa Clara, CA). The mRNA library construction were performed by SMARTer Ultra Low RNA Kit for Illumina Sequencing pherchased from Clontech Laboratory (Mountain View, CA) using manufacturer's protocol. And then, the validated libraries were applied to the 75 bp, paired end sequencing process of HiSeq 2500 (Illumina) to generate raw sequencing FASTQ data files. All sequencing procedures from RNA extraction to FASTQ generation were carried out by YCGA (Yale Center for Genome Analysis, West Haven, CT). The quality control check of FASTQ files was carried out by FastQC:ReadQC (version 0.52) analysis in Galaxy web-based platform and the sequences passed on M-bM-^@M-^Xper base sequence qualityM-bM-^@M-^Y were mapped on the UCSC mm10 mouse genome (Dec. 2011 Mus musculus assembly (Genome Reference Consortium Mouse Build 38)) using Tophat-2.0.9 including Bowtie-2-2.1.0 and Samtools-0.1.18. As the option of library type in Tophat, M-bM-^@M-^Xfr-unstrandedM-bM-^@M-^Y for Illumina TruSeq protocol was set as the default and the option of M-bM-^@M-^Xno-novel-juncsM-bM-^@M-^Y was chosen to quantify the reference annotation only. Cuffdiff, a separate program of Cufflinks-2.1.1, analyzed the differentially regulated transcriptional level among the reference transcriptoms of our samples and the results were visualized and further manipulated by CummeRbund-2.12.
2014-03-06 | E-GEOD-55621 | biostudies-arrayexpress
Project description:Neural stem cells (NSCs) continuously produce new neurons within the adult mammalian hippocampus. However, this process declines with age and this decline correlates with defects in cognitive function and mood. Molecular mechanisms that activate quiescent NSCs to generate progenitor cells in vivo remain poorly understood. Here we show that adult hippocampal NSCs express VEGFR3, a key regulator of vascular and neural development, and are activated by the VEGFR3 ligand VEGF-C to enter the cell cycle and convert into progenitor cells. Conditional deletion of Vegfr3 in NSCs leads to a decline in hippocampal neurogenesis. Functionally, this is associated with increased anxiety behavior and compromised NSC activation in response to VEGF-C and physical activity. These findings establish VEGFR3 expression as a hallmark of adult mouse NSCs and demonstrate a specific requirement for VEGF-C/VEGFR signaling in NSC activation. Enhancing VEGFR3 signaling by VEGF-C may improve neurogenesis and mood during aging.
2014-03-06 | GSE55621 | GEO
Project description:This is a spatially averaged multiscale mathematical model of tumor angiogenesis. The model describes the dynamics of VEGF, Ang1, Ang2, and PDGF, coupled with those of mature and immature endothelial cells and pericyte cells.
2019-11-13 | MODEL1911130007 | BioModels
Project description:PI3K-mediated crosstalk between angiopoietin and vascular endothelial growth factor C signaling pathways is required for lymphangiogenesis
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Project description:In this work we have induced meningeal lymphatic ablation by decreasing the circulating levels of VEGF-C and -D (VEGF-C/D trap), via injection of an AAV9 expressing domains 1 to 3 of murine VEGFR3 coupled to an Ig domain (VEGF-C/D trap). Control mice were injected with an AAV9 expressing domains 4 to 7 of murine VEGFR3 coupled to an Ig domain (controls). 5 weeks upon the initial injections, animals were perfused, and the forebrain tissue was collected and processed for single-cell RNA sequencing (10x Genomics).
2024-07-31 | GSE230709 | GEO
Project description:The pre-metastatic niche is a pre-determined site of metastases, awaiting the influx of tumor cells. Here we demonstrate that the calcineurin-NFAT pathway is activated specifically in lung endothelium prior to the detection of tumor cells that preferentially metastasize to the lung. We previously showed that DSCR-1 functions in a negative feedback loop to attenuate calcineurin signaling. Upregulation of the calcineurin pathway via loss of Dscr-1 leads to a significant increase in lung metastasis due to the increased expression of a newly identified NFAT target, Angiopoietin (Ang)-2. An increase in VEGF levels specifically in the lung versus other organ microenvironments triggers a threshold of calcineurin-NFAT signaling that transactivates Ang2 in lung endothelium. Further, we demonstrate that overexpression of DSCR-1 or the Ang-2 receptor, soluble Tie2, prevents activation of the lung endothelium inhibiting lung metastases in our mouse models. Our studies provide insights into mechanisms underlying angiogenesis in the pre-metastatic niche and offers novel targets for lung metastases. Whole lung total RNA were harvested from wildtype or Dscr-1 null mutation mice (C57BL6/J background), and subjected to Affymetrix Mouse 430 2.0 array in duplicate conditions. Alternatively, primary cultured human lung endothelial cells (LONZA) were transfected with either siRNA, control or DSCR-1, or adenovirus expressing DSCR-1 or mock control. Adenovirally transfected lung endothelial cells were serum-starved (EBM-2 (LONZA) plus 0.5% FBS) and treated with 50ng/ml VEGF for indicated time points. After the treatments, total RNA was harvested and subjected to Affymetrix Human U133 Plus 2.0 array.
2015-01-01 | E-GEOD-48841 | biostudies-arrayexpress
Project description:Prostate cancer is the most common cancer in men and is often associated with distant metastasis in its later stages. Lymphangiogenesis has been identified as a critical factor in cancer metastasis, and the adipokine apelin has been implicated in cancer progression and metastasis. However, researchers have yet to elucidate the mechanisms by which apelin regulates the key lymphangiogenic factor, Vascular Endothelial Growth Factor-C (VEGF-C), to promote distant metastasis in prostate cancer. This study identified a strong positive correlation between apelin levels and prostate cancer metastasis. Apelin stimulation was shown to upregulate VEGF-C expression, promoting the formation of new lymphatic vessels. Apelin treatment was also shown to downregulate miR-196a-5p expression via the proto-oncogene tyrosine kinase c-Src (c-Src) and Signal transducer and activator of transcription 3 (STAT3) signaling pathways, which regulates VEGF-C expression and lymphangiogenesis in prostate cancer cell lines. In an orthotopic mouse model, apelin inhibition prevented lymphangiogenesis and distant metastasis. These findings suggest that targeting apelin could be a promising therapeutic approach to preventing prostate cancer metastasis and lymphangiogenesis
2024-11-09 | GSE281393 | GEO
Project description:Angiopoietin-Tie1 signaling is required for lymphatic vascular integrity and both ANGPT2 and TIE1 genetic variants have been associated with lymphedema in patients1, 2. Concurrent with growth-factor signaling, mechanical forces sensed by lymphatic endothelial cells (LECs) are also needed to regulate lymphatics3, 4. How these two pathways might interact in the lymphatic system is unknown. Here, we identified a regulatory network in LECs linking activation of the mechanosensory channel, PIEZO1 to Angiopoietin-Tie signaling and repression of a downstream FOXO1 transcriptional response. RNAseq analysis of dermal LECs from Tie1-deficient embryos showed persistent FOXO1 activity with downregulation of LEC-associated genes including Ccl21a, Foxc2, Gata2 and Gja4, as well as increased expression of the mechanosensory channel, Piezo1. Activation of PIEZO1 in human dermal LECs (HDLECs) by the small molecule agonist, Yoda1, triggered exocytosis of the Tie ligand, Angiopoietin-2 (ANGPT2), activation of Tie/AKT/PI3K signaling and export of FOXO1 out of the nucleus. Our data identify a novel molecular pathway linking mechano-transduction to ANGPT2-Tie1 activity and dynamic modulation of FOXO1 activity needed for patterning and function of the lymphatic system
2024-03-05 | GSE211849 | GEO
Project description:The pre-metastatic niche is a pre-determined site of metastases, awaiting the influx of tumor cells. Here we demonstrate that the calcineurin-NFAT pathway is activated specifically in lung endothelium prior to the detection of tumor cells that preferentially metastasize to the lung. We previously showed that DSCR-1 functions in a negative feedback loop to attenuate calcineurin signaling. Upregulation of the calcineurin pathway via loss of Dscr-1 leads to a significant increase in lung metastasis due to the increased expression of a newly identified NFAT target, Angiopoietin (Ang)-2. An increase in VEGF levels specifically in the lung versus other organ microenvironments triggers a threshold of calcineurin-NFAT signaling that transactivates Ang2 in lung endothelium. Further, we demonstrate that overexpression of DSCR-1 or the Ang-2 receptor, soluble Tie2, prevents activation of the lung endothelium inhibiting lung metastases in our mouse models. Our studies provide insights into mechanisms underlying angiogenesis in the pre-metastatic niche and offers novel targets for lung metastases.
2015-01-01 | GSE48841 | GEO
Project description:In primary melanoma, the amount of VEGF-C expression and lymphangiogenesis predict the probability of metastasis to sentinel nodes, but conditions boosting VEGF-C expression in melanoma are poorly characterized. By comparative mRNA expression analysis of a set of 22 human melanoma cell lines, we found a striking negative correlation between VEGF-C and MITF expression, which was confirmed by data mining in GEO databases of human melanoma Affymetrix arrays. Moreover, in human patients, high VEGF-C, and low MITF levels in primary melanoma significantly correlated with the chance of metastasis. Pathway analysis disclosed the respective JNK- and p38/MAPK activities as being responsible for the inverse regulation of VEGF-C and MITF. Predominant JNK signaling results in a VEGF-Clow/MITFhigh phenotype, these melanoma cells are highly proliferative, show low mobility and are poorly lymphangiogenic. Predominant p38 signaling results in a VEGF-Chigh/MITFlow phenotype, corresponding to a slowly cycling, highly mobile, lymphangiogenic and metastatic melanoma.
2015-10-01 | GSE71122 | GEO