Control of coronary lymphangiogenesis by epicardial VEGFC/D
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ABSTRACT:
PROVIDER: PRJNA1200685 | ENA |
REPOSITORIES: ENA
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Project description:The contractile ability of the mammalian heart critically relies on blood coronary circulation, essential to provide oxygen and nutrients to myocardial cells. In addition, the lymphatic vasculature is essential for the myocardial immune response, extracellular fluid homeostasis and response to injury. Recent studies identified different origins of coronary lymphatic endothelial cells, however, the cues that govern coronary lymphangiogenesis remain unknown. Here we show that the coronary lymphatic vasculature develops in intimate contact with the epicardium and with epicardial-derived cells. The epicardium expresses the lymphangiogenic cytokine VEGFC and its conditional elimination from the epicardium abrogates coronary lymphatic vasculature development. Interestingly, VEGFD is also expressed in the epicardium and cooperates with VEGFC in coronary lymphangiogenesis, but it does so only in females, uncovering an unsuspected sex-specific role for this cytokine. These results identify a role for the epicardium/subepicardium as a signalling niche required for coronary lymphangiogenesis and VEGFC/D as essential mediators of this role.
2025-02-05 | GSE284800 | GEO
Project description:Proteolytical processing of the growth factor VEGFC through the concerted activity of CCBE1 and ADAMTS3 is required for lymphatic development to occur. How these factors act together in time and space, and which cell types produce these factors is not understood. Here we assess the function of Adamts3 and the related protease Adamts14 during zebrafish lymphangiogenesis and show both proteins to be able to process Vegfc. Only the simultaneous loss of both protein functions results in lymphatic defects identical to vegfc loss-of-function situations. Cell transplantation experiments demonstrate neuronal structures and/or fibroblasts to constitute cellular sources not only for both proteases but also for Ccbe1 and Vegfc. We further show that it is the local restriction of Vegfc maturation which is needed to trigger normal lymphatic sprouting and directional migration. Our data provide a single-cell resolution model for establishing secretion and processing hubs for Vegfc during developmental lymphangiogenesis
2020-04-28 | GSE146923 | GEO
Project description:The development of a differentiated and functional vasculature requires coordinated control of cell fate specification, lineage differentiation and vascular network growth. Cellular proliferation is spatiotemporally regulated in developing vessel networks but how this is achieved and differentially controlled in specific lineages is unknown. Using a zebrafish forward genetic screen for mutants that form blood vessels but fail to form lymphatic vessels, we uncovered a mutant for the RNA helicase Ddx21. Ddx21 cell-autonomously regulates the early development of lymphatic endothelial cells. Ddx21 is essential for Vegfc-Vegfr3 driven endothelial cell proliferation. Ddx21 is an established regulator of ribosomal RNA transcription and in the absence of Ddx21, mutant lymphatic endothelial cells show reduced ribosome biogenesis. Ultimately, loss of Ddx21 leads to a p53-p21 dependent cell cycle arrest that blocks embryonic lymphangiogenesis. Thus, the RNA helicase Ddx21 coordinates the endothelial cell proliferative response to Vegfc-Vegfr3 signalling by balancing ribosome biogenesis and p53-p21 signalling. This mechanism may have therapeutic potential in diseases of excessive lymphangiogenesis such as in cancer metastasis or lymphatic malformation.
2021-09-09 | GSE179868 | GEO
Project description:The development of a differentiated and functional vasculature requires coordinated control of cell fate specification, lineage differentiation and vascular network growth. Cellular proliferation is spatiotemporally regulated in developing vessel networks but how this is achieved and differentially controlled in specific lineages is unknown. Using a zebrafish forward genetic screen for mutants that form blood vessels but fail to form lymphatic vessels, we uncovered a mutant for the RNA helicase Ddx21. Ddx21 cell-autonomously regulates the early development of lymphatic endothelial cells. Ddx21 is essential for Vegfc-Vegfr3 driven endothelial cell proliferation. Ddx21 is an established regulator of ribosomal RNA transcription and in the absence of Ddx21, mutant lymphatic endothelial cells show reduced ribosome biogenesis. Ultimately, loss of Ddx21 leads to a p53-p21 dependent cell cycle arrest that blocks embryonic lymphangiogenesis. Thus, the RNA helicase Ddx21 coordinates the endothelial cell proliferative response to Vegfc-Vegfr3 signalling by balancing ribosome biogenesis and p53-p21 signalling. This mechanism may have therapeutic potential in diseases of excessive lymphangiogenesis such as in cancer metastasis or lymphatic malformation.
2021-09-09 | GSE158566 | GEO
Project description:Recent reports have suggested a protective role for vascular endothelial growth factor C (VEGFC) during acute cardiac lymphangiogenesis post MI. Glinton et al. report that defective efferocytosis by macrophages after experimental MI leads to a reduction in cardiac lymphangiogenesis and Vegfc expression.
2022-03-31 | GSE196866 | GEO
Project description:Recent reports have suggested a protective role for vascular endothelial growth factor C (VEGFC) during acute cardiac lymphangiogenesis post MI. Glinton et al. report that defective efferocytosis by macrophages after experimental MI leads to a reduction in cardiac lymphangiogenesis and Vegfc expression.
2022-03-31 | GSE196865 | GEO
Project description:While colorectal cancer liver metastasis (CRCLM) is major cause of death of colorectal cancer, the mechanism of intrahepatic dissemination (trans-lymphatic metastasis) is not fully elucidated. Lymphangiogenesis can be the mechanism of the dissemination, but there are few evidences to prove it. In this study, we attempted to clarify the mechanism using syngeneic murine CRCLM model, especially focusing on vascular endothelial growth factor C (VEGFC), a promoter of lymphangiogenesis. We confirmed that 1) intrahepatic metastasis of CRCLM via lymphatic vessels was seen and lymphangiogenesis was upregulated in the CRCLM-bearing liver, 2) the degree of lymphangiogenesis and CRCLM was significantly correlated with the expression of VEGFC in colorectal cancer (CRC) cells and 3) macrophage inflammatory protein-1α (MIP-1α) was released from CRC cells under the stimulation of VEGFC and induced migration of immature bone marrow derived cells into the liver and differentiation into macrophage, which promoted dissemination of CRCLM. These findings suggest the possibility of therapeutic strategy targeting VEGFC / MIP-1α for diminishing CRCLM. In conclusion, VEGFC in CRC cells promoted trans-lymphatic metastasis of CRCLM by upregulation of lymphangiogenesis directly and indirectly via induction of macrophages derived from bone marrow cells.
2018-09-30 | GSE113235 | GEO
Project description:We took samples of subcutaneous adipose tissue from the sternum (SAT) and epicardial adipose tissue (EAT) from a site adjacent to the right coronary artery in cases with coronary disease and controls without coronary disease. Cases had significant coronary disease and were undergoing coronary artery bypass surgery. Controls all had coronary angiograms and did not have significant coronary disease.
2018-10-04 | GSE120774 | GEO
Project description:Recent studies have suggested that promoting lymphangiogenesis enhances cardiac repair following injury, but it is unknown whether lymphangiogenesis is required for cardiac regeneration. Here, we describe the anatomical distribution, regulation and function of the cardiac lymphatic network in a highly regenerative zebrafish model system using transgenic reporter lines and loss-of-function approaches.To understand the transcriptional profile of the model, we performed RNA-seq on cardiac ventricles from control and mutant (vegfc(hy-/-);vegfd(-/-)) ventricles. Overall, vegfc(hy-/-;vegfd-/-) mutant ventricles were characterized by an up-regulation of pathways related to sphingolipid and phospholipid metabolism, translation, protein maturation and nonsense mediated decay compared to control hearts. Our findings suggest that lymphatics vasculature play a role in lipid transport and when lymphatic function is compromised in vegfch(y-/-;vegfd-/-) mutant, there are consequences to sphingolipid and phospholipid metabolism. Vegfc(hy-/-;vegfd-/-) mutant ventricles were not characterized by an enrichment of genes pathways implicated in pathological hypertrophy. This finding suggests that the absence of cardiac lymphatics induced a physiological rather than pathological cardiac hypertrophy.
2019-09-03 | GSE133130 | GEO
Project description:Aberrant repair after musculoskeletal injury is one of the most costly and common clinical scenarios in health care. While advances in our understanding of the key cells and pathways during the repair process have improved, there remains a gap in knowledge of the key progenitor cells and their interaction with the surrounding microenvironment. Heterotopic ossification (HO) is a pathological process caused by aberrant cell-fate determination resulting in the formation of bone in non-skeletal tissues after musculoskeletal injury. While the involvement of blood vessels in musculoskeletal repair is well-documented, the role of lymphatic vessels and the cells responsible for their ingrowth in musculoskeletal tissues during both homeostasis and after injury remains poorly understood. In this study, we employed a mouse model of traumatic HO to investigate lymphangiogenesis during musculoskeletal injury and repair and to uncover the key progenitor cells responsible to stimulate lymphangiogenesis and undergo aberrant cell fate differentiation. Our findings demonstrated that musculoskeletal injury triggered lymphangiogenesis at the injury site, including invasion of lymphatic vessels into the tendon proper. This increased lymphangiogenesis was driven by elevated levels of active Vascular Endothelial Growth Factor C (VEGF-C) one-week post-injury. Through single-cell transcriptomic analyses, we identified mesenchymal progenitor cells (MPCs) as a source of Vegfc following injury as well as the source of enzymes responsible for activating VEGF-C. These Vegfc-expressing MPCs underwent osteochondral differentiation and actively contributed to the formation of HO following injury. Notably, Vegfc haploinsufficiency resulted in a near 50% reduction in lymphangiogenesis and HO formation. Collectively, these findings suggest that MPC expression of VEGF-C and its activating enzymes in response to soft tissue trauma play a critical role in stimulating pathologic lymphatic vessel growth. Furthermore, Vegfc expressing MPCs undergo aberrant osteochondral differentiation responsible for HO. Targeting Vegfc expression and Vegfc-expressing progenitors therapeutically could potentially mitigate pathologic lymphangiogenesis, preventing aberrant tissue repair and subsequent HO formation.
2024-06-13 | GSE255500 | GEO