Control of endothelial sprouting by a Tel–CtBP complex

Roukens, M. Guy; Alloul-Ramdhani, Mariam; Baan, Bart; Kobayashi, Kazuki; Peterson-Maduro, Josi; Dam, Hans van; Schulte‐Merker, Stefan; Baker, David A.

doi:10.1038/ncb2096

Cited by 50 publications

(48 citation statements)

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“…Previous studies identified a role for another ETS factor, TEL (ETV6), in the repression, rather than the activation, of DLL4 (Roukens et al, 2010). In this case, TEL bound to the DLL4 promoter under basal conditions to recruit a co-repressor protein, CTBP.…”

Section: Discussionmentioning

confidence: 99%

Dynamic regulation of VEGF-inducible genes by an ERK-ERG-p300 transcriptional network

et al. 2017

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The transcriptional pathways activated downstream of vascular endothelial growth factor (VEGF) signaling during angiogenesis remain incompletely characterized. By assessing the signals responsible for induction of the Notch ligand delta-like 4 (DLL4) in endothelial cells, we find that activation of the MAPK/ERK pathway mirrors the rapid and dynamic induction of DLL4 transcription and that this pathway is required for DLL4 expression. Furthermore, VEGF/ERK signaling induces phosphorylation and activation of the ETS transcription factor ERG, a prerequisite for DLL4 induction. Transcription of DLL4 coincides with dynamic ERG-dependent recruitment of the transcriptional co-activator p300. Genome-wide gene expression profiling identified a network of VEGF-responsive and ERG-dependent genes, and ERG chromatin immunoprecipitation (ChIP)-seq revealed the presence of conserved ERG-bound putative enhancer elements near these target genes. Functional experiments performed in vitro and in vivo confirm that this network of genes requires ERK, ERG and p300 activity. Finally, genome-editing and transgenic approaches demonstrate that a highly conserved ERG-bound enhancer located upstream of HLX (which encodes a transcription factor implicated in sprouting angiogenesis) is required for its VEGFmediated induction. Collectively, these findings elucidate a novel transcriptional pathway contributing to VEGF-dependent angiogenesis.

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Section: Discussionmentioning

confidence: 99%

Dynamic regulation of VEGF-inducible genes by an ERK-ERG-p300 transcriptional network

et al. 2017

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“…Three-dimensional system have been developed to study sprouting angiogenesis in vitro, for example, endothelial sprouting from a planar endothelium into bulk collagen gel (24), lateral endothelial sprouting into a collagen gel isolated between two microfluidic channels formed in PDMS silicone (25), and 3D endothelial sprouting from microbead supports in a bulk gel (26). None of these systems allows for the initiation of angiogenesis from native-like vessels with luminal flow and simultaneous control of the chemical and cellular microenvironment of the endothelium.…”

Section: Resultsmentioning

confidence: 99%

In vitro microvessels for the study of angiogenesis and thrombosis

Zheng

Chen

Craven

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

796

842

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Microvascular networks support metabolic activity and define microenvironmental conditions within tissues in health and pathology. Recapitulation of functional microvascular structures in vitro could provide a platform for the study of complex vascular phenomena, including angiogenesis and thrombosis. We have engineered living microvascular networks in three-dimensional tissue scaffolds and demonstrated their biofunctionality in vitro. We describe the lithographic technique used to form endothelialized microfluidic vessels within a native collagen matrix; we characterize the morphology, mass transfer processes, and long-term stability of the endothelium; we elucidate the angiogenic activities of the endothelia and differential interactions with perivascular cells seeded in the collagen bulk; and we demonstrate the nonthrombotic nature of the vascular endothelium and its transition to a prothrombotic state during an inflammatory response. The success of these microvascular networks in recapitulating these phenomena points to the broad potential of this platform for the study of cardiovascular biology and pathophysiology.tissue engineering | regenerative medicine | microfluidics | cancer | blood T he microvasculature is an extensive organ that mediates the interaction between blood and tissues. It defines the biological and physical characteristics of the microenvironment within tissues and plays a role in the initiation and progression of many pathologies, including cancer (1) and cardiovascular diseases (2, 3). Conventional planar cultures fail to recreate the in vivo physiology of the microvasculature with respect to three-dimensional (3D) geometry (lumens and axial branching points), and interactions of endothelium with perivascular cells, extracellular tissue and blood flow (4). Studies of the microvasculature in vivo allow only limited control of physical, chemical, and biological parameters influencing the microvasculature and present challenges with respect to observation (5). In vitro cultures that produce tubular vessels within 3D matrices will aid in elucidation of the roles of the microvasculature in health and disease. Important progress has been made toward this goal: Biologically derived or synthetic materials have been used to generate macrovessel tubes (6) and endothelialized microtubes (7); cellular self-assembly has been used to generate random microvasculature (8); microfabrication has been used to define complex geometries in hydrogels at the micro-scale (9); and distributions of cells and biochemical factors within 3D scaffolds (10). Of particular note, the group of Tien has pioneered the use of collagen to template the growth of vascular endothelium (7, 11) and demonstrated appropriate permeability (7), response to cyclic AMP (12), and differential properties as a function of the luminal shear stress and composition of the medium (13). Nonetheless, prior methodologies have been unable to produce endothelialized networks that can undergo substantial remodeling via angiogenesis; elucidate the ...

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“…Results indicate that KROX (a component of the early growth response genes [EGR] family) regulates a significant amount of the genes whose methylation status correlates with blood flow, capillary density, and arteriole counts (418, 1979, and 369, respectively). 14,15 Moreover, 536 genes associated with blood flow, 2805 genes associated with capillary density, and 460 genes associated with arteriole counts are regulated by MYCassociated zinc finger protein (MAZ), which is involved in cell proliferation and mediates vascular endothelial growth factor (VEGF)-induced angiogenesis. 16 Hence, interference of DNA methylation with KROX/EGR1 and MAZ might result in large effects on gene transcription and possibly on promotion of tissue repair by SV-APCs.…”

Section: Correlation Between Dna Methylation Profile Of Sv-apcs and Pmentioning

confidence: 99%

Epigenetic Profile of Human Adventitial Progenitor Cells Correlates With Therapeutic Outcomes in a Mouse Model of Limb Ischemia

Gubernator

Slater

Spencer

et al. 2015

ATVB

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Objective— We investigated the association between the functional, epigenetic, and expressional profile of human adventitial progenitor cells (APCs) and therapeutic activity in a model of limb ischemia. Approach and Results— Antigenic and functional features were analyzed throughout passaging in 15 saphenous vein (SV)–derived APC lines, of which 10 from SV leftovers of coronary artery bypass graft surgery and 5 from varicose SV removal. Moreover, 5 SV-APC lines were transplanted (8×10 5 cells, IM) in mice with limb ischemia. Blood flow and capillary and arteriole density were correlated with functional characteristics and DNA methylation/expressional markers of transplanted cells. We report successful expansion of tested lines, which reached the therapeutic target of 30 to 50 million cells in ≈10 weeks. Typical antigenic profile, viability, and migratory and proangiogenic activities were conserved through passaging, with low levels of replicative senescence. In vivo, SV-APC transplantation improved blood flow recovery and revascularization of ischemic limbs. Whole genome screening showed an association between DNA methylation at the promoter or gene body level and microvascular density and to a lesser extent with blood flow recovery. Expressional studies highlighted the implication of an angiogenic network centered on the vascular endothelial growth factor receptor as a predictor of microvascular outcomes. FLT-1 gene silencing in SV-APCs remarkably reduced their ability to form tubes in vitro and support tube formation by human umbilical vein endothelial cells, thus confirming the importance of this signaling in SV-APC angiogenic function. Conclusions— DNA methylation landscape illustrates different therapeutic activities of human APCs. Epigenetic screening may help identify determinants of therapeutic vasculogenesis in ischemic disease.

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Control of endothelial sprouting by a Tel–CtBP complex

Cited by 50 publications

References 48 publications

Dynamic regulation of VEGF-inducible genes by an ERK-ERG-p300 transcriptional network

Dynamic regulation of VEGF-inducible genes by an ERK-ERG-p300 transcriptional network

In vitro microvessels for the study of angiogenesis and thrombosis

Epigenetic Profile of Human Adventitial Progenitor Cells Correlates With Therapeutic Outcomes in a Mouse Model of Limb Ischemia

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