Affinage

DLL4

Delta-like protein 4 · UniProt Q9NR61

Length
685 aa
Mass
74.6 kDa
Annotated
2026-04-28
100 papers in source corpus 45 papers cited in narrative 45 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DLL4 is a transmembrane Notch ligand that functions as a central regulator of angiogenesis, vascular patterning, and cell fate specification across multiple tissues. In endothelial cells, VEGF induces DLL4 expression via PI3K/Akt signaling, and DLL4 activates Notch1 on neighboring cells through lateral inhibition to suppress tip cell formation and limit excessive sprouting; this negative feedback couples angiogenic sprouting to arterial specification, with Jagged1 serving as a competitive antagonist whose activity is modulated by Fringe glycosyltransferases (PMID:17296940, PMID:19524514, PMID:12482957, PMID:28714968). DLL4 transcription is controlled combinatorially by Foxc1/2, SoxF factors, Notch/RBPJ autoregulatory inputs, Wnt/β-catenin, and HIF-1α, and its subcellular presentation at adherens junctions requires the scaffold protein MPDZ (PMID:18545664, PMID:23818617, PMID:20627076, PMID:17045587, PMID:29620522). Beyond the vasculature, DLL4 together with DLL1 maintains intestinal stem cells, regulates lymphatic vessel integrity and fat absorption, drives thymus-seeding progenitor generation from bone marrow mesenchymal cells, directs macrophage proinflammatory polarization, and controls skeletal muscle mass via a paracrine endothelial DLL4–muscular Notch2 axis (PMID:21238454, PMID:26529256, PMID:25918341, PMID:30586693, PMID:35228746). Heterozygous loss-of-function mutations in DLL4 cause autosomal-dominant Adams-Oliver syndrome (PMID:26299364).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2003 High

    Identifying how DLL4 expression is induced established it as a VEGF-responsive gene in arterial endothelium, linking growth factor signaling to Notch pathway activation.

    Evidence VEGF stimulation of arterial endothelial cells with PI3K/Akt and MAPK pathway inhibitors; 3D angiogenesis assays

    PMID:12482957

    Open questions at the time
    • Whether other growth factors besides VEGF induce DLL4 in non-endothelial contexts
    • No structural basis for DLL4-Notch interaction at this point
  2. 2006 High

    Demonstration that DLL4 blockade causes endothelial hyperproliferation and that hypoxia/HIF-1α directly induces DLL4 established DLL4-Notch as a negative regulator of vascular growth and placed it downstream of both VEGF and oxygen sensing.

    Evidence Anti-DLL4 neutralizing antibody in tumor models; HIF-1α overexpression/knockdown in endothelial progenitors with promoter analysis

    PMID:17045587 PMID:17183323

    Open questions at the time
    • Whether DLL4 acts in trans only or also in cis at this stage
    • Identity of downstream effectors beyond Hey1/Hey2
  3. 2007 High

    Showing that DLL4 is dynamically induced in retinal tip cells and limits sprouting via Notch established the lateral inhibition model in postnatal angiogenesis.

    Evidence DLL4-Fc and blocking antibody administration; Dll4 haploinsufficient mice; postnatal retinal vascular analysis

    PMID:17296940

    Open questions at the time
    • How DLL4 oscillations relate to tip/stalk selection
    • Whether Notch receptor specificity matters in retinal endothelium
  4. 2008 High

    Identification of Foxc1/Foxc2 as direct transcriptional activators of the DLL4 promoter, with Foxc2 physically interacting with the Su(H)/NICD complex, revealed an integrative node linking VEGF-ERK/PI3K signaling to DLL4 transcription.

    Evidence Promoter reporter assays with Foxc binding element mutagenesis; co-immunoprecipitation of Foxc2 with NICD; siRNA knockdown in endothelial cells

    PMID:18545664

    Open questions at the time
    • Whether Foxc factors are required in all vascular beds or only in specific territories
    • No ChIP-seq for genome-wide Foxc-DLL4 regulatory landscape
  5. 2009 High

    The discovery that Jagged1 antagonizes DLL4-Notch signaling through competition modulated by Fringe glycosyltransferases resolved how two Notch ligands produce opposing angiogenic outcomes in the same tissue.

    Evidence Genetic mouse models with Fringe manipulation; in vivo angiogenesis assays

    PMID:19524514

    Open questions at the time
    • Quantitative binding affinities of glycosylated vs. unglycosylated Notch for DLL4 vs. Jagged1
    • Whether Fringe modulation operates identically in lymphatic endothelium
  6. 2010 High

    Wnt/β-catenin was added as a direct transcriptional inducer of DLL4, linking two major developmental signaling pathways in arteriovenous specification.

    Evidence Endothelial-specific β-catenin gain-of-function mice; Dll4 promoter chromatin/transcriptional analysis

    PMID:20627076

    Open questions at the time
    • Whether β-catenin acts on the same enhancers as RBPJ/SoxF or distinct regulatory elements
  7. 2011 High

    Combinatorial knockout of Dll1 and Dll4 in intestinal epithelium revealed that these two ligands are the essential physiological Notch activators maintaining intestinal stem cells, expanding DLL4 function beyond vascular biology.

    Evidence Vil-Cre-ERT2 inducible single and double conditional knockouts in mice; stem cell lineage analysis

    PMID:21238454

    Open questions at the time
    • Relative individual contributions of DLL1 vs. DLL4 to stem cell maintenance
    • Whether DLL4 acts on Lgr5+ stem cells directly or through Paneth cells
  8. 2011 High

    DLL4-Notch1 signaling was shown to regulate postnatal lymphatic sprouting via EphrinB2-dependent VEGFR3 signaling, and integrin-laminin adhesion was placed upstream of DLL4 induction, adding extracellular matrix cues to the regulatory network.

    Evidence Function-blocking antibodies against Notch1/Dll4 in lymphangiogenesis models; integrin siRNA knockdown with sprouting assays

    PMID:21474814 PMID:21700774

    Open questions at the time
    • Whether integrin-mediated DLL4 induction operates in lymphatic endothelium
    • Molecular mechanism connecting integrin signaling to DLL4 transcription
  9. 2012 High

    Multiple discoveries extended DLL4-Notch to immune and hematopoietic biology: DLL4 was shown to regulate thymic DC/Treg homeostasis, post-transcriptionally controlled by miR-30, and its ectopic expression in erythroblasts (upon LRF loss) disrupted HSC maintenance.

    Evidence Anti-Dll4 blockade in thymic progenitors; miR-30 target-protector in zebrafish; erythroblast-specific Lrf KO mice with HSC assays

    PMID:22547652 PMID:23086751 PMID:23134786

    Open questions at the time
    • Whether miR-30 regulation of DLL4 operates in non-endothelial cells
    • Mechanism by which erythroblast DLL4 reaches HSCs in the niche
  10. 2013 High

    Characterization of arterial-specific enhancers showed that SoxF factors and RBPJ/NICD combinatorially control DLL4 expression, with loss of both inputs ablating arterial identity, providing the cis-regulatory logic for arterial DLL4.

    Evidence Enhancer mutagenesis in transgenic mouse and zebrafish reporters; combined Sox7/Sox18/Rbpj knockdown

    PMID:23818617

    Open questions at the time
    • Whether these enhancers operate in coronary or lymphatic arterial beds
    • Chromatin accessibility dynamics at these enhancers during de novo arteriogenesis
  11. 2015 High

    DLL4 was established in lymphatic vessel maintenance, bone marrow HSC niche signaling, coronary arterial development, and as unique among Delta ligands for potent cis-inhibition of Notch, while human genetics linked DLL4 haploinsufficiency to Adams-Oliver syndrome.

    Evidence Lymphatic EC-specific Dll4 KO with fat absorption assays; Ocn+ mesenchymal cell Dll4 deletion; Dll1Dll4ki knock-in; DLL4 mutation sequencing in AOS families

    PMID:25918341 PMID:26114479 PMID:26299364 PMID:26529256

    Open questions at the time
    • Functional validation of individual AOS-associated DLL4 missense mutations
    • How DLL4 cis-inhibition is structurally distinct from DLL1
    • Whether released/soluble DLL4 contributes to niche signaling
  12. 2016 High

    Live imaging revealed that oscillatory DLL4 expression dynamics drive branching heterogeneity, with pathological VEGF or DLL4 levels synchronizing oscillations and switching from branching to expansion, adding a dynamic systems-level layer to DLL4 function.

    Evidence Live imaging of Dll4 in mouse retina and ES cell-derived sprouts; DLL4 overexpression; Notch inhibition

    PMID:27074663

    Open questions at the time
    • Molecular clock or feedback controlling DLL4 oscillation period
    • Whether oscillation dynamics apply in non-retinal vascular beds
  13. 2018 High

    MPDZ was identified as a scaffold linking DLL4 to adherens junctions via Nectin-2, and ERK-dependent FOXC2 phosphorylation was shown to mediate TLR4-induced DLL4 transcription, refining understanding of DLL4 subcellular presentation and inflammatory induction.

    Evidence Co-immunoprecipitation of MPDZ-DLL4-Nectin-2; MPDZ KO vascular phenotype; FOXC2 ChIP at DLL4 promoter after LPS

    PMID:29380370 PMID:29620522

    Open questions at the time
    • Whether MPDZ is required in all DLL4-expressing cell types
    • How MPDZ-mediated junctional localization affects signaling kinetics
  14. 2019 High

    Multiple studies revealed DLL4 operates in macrophage biology (proinflammatory polarization via indoxyl sulfate/USP5 stabilization, atherosclerosis), diabetic wound healing (keratinocyte DLL4-Notch1 loop), and coronary development (Dll4-Jag1-EphrinB2 cascade), while LPA4/6-YAP/TAZ was found to repress DLL4.

    Evidence Macrophage-specific DLL4 KO in atherosclerosis model; keratinocyte-specific Notch1 KO in diabetic wounds; endocardial Dll4/Jag1 conditional KOs; endothelial Lpa4/Lpa6 double KO mice

    PMID:30586693 PMID:30886104 PMID:31335323 PMID:31789590

    Open questions at the time
    • Whether USP5-mediated DLL4 stabilization occurs in non-macrophage contexts
    • How YAP/TAZ mechanistically repress DLL4 transcription at the promoter level
  15. 2020 Medium

    RHOQ was identified as a Notch-induced GTPase required for NICD nuclear translocation, creating a feed-forward amplification loop; separately, DLL4 was shown to restrict intra-aortic hematopoietic cluster formation by limiting hemogenic cell recruitment.

    Evidence RHOQ siRNA/overexpression with subcellular localization and Notch reporter assays; live imaging of organotypic aortic slices with Dll4 blockade

    PMID:32149421 PMID:32506201

    Open questions at the time
    • RHOQ mechanism validated primarily by siRNA in a single lab
    • Whether RHOQ functions downstream of DLL4-Notch specifically or all Notch ligands
  16. 2022 High

    A paracrine, non-contact-dependent endothelial DLL4–muscular Notch2 axis was discovered to regulate skeletal muscle mass, and affinity-matured DLL4 (DeltaMAX) demonstrated dose/format-dependent agonist-antagonist duality, revealing new signaling modalities.

    Evidence Mouse disuse/diabetic atrophy models with Dll4-Notch2 inhibition; directed evolution producing DeltaMAX with 500–1000-fold affinity increase; reporter and differentiation assays

    PMID:35228746 PMID:36050494

    Open questions at the time
    • Whether released DLL4 signals in a soluble form or via exosomes in muscle
    • Structural basis for DeltaMAX agonist/antagonist switch
  17. 2024 High

    Macrophage DLL4 was shown to drive vascular smooth muscle cell senescence and plaque instability via palmitic acid induction, extending macrophage DLL4 from inflammation to atherosclerotic tissue remodeling.

    Evidence Macrophage-specific DLL4 conditional KO in atherosclerotic mice; VSMC senescence assays; human cohort correlation

    PMID:38346959

    Open questions at the time
    • Whether DLL4-induced VSMC senescence is Notch1- or Notch3-dependent
    • Upstream lipid-sensing mechanism linking palmitic acid to DLL4 transcription

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of DLL4's unique cis-inhibitory potency versus DLL1, the precise mechanisms governing DLL4 oscillation dynamics, whether released/exosomal DLL4 represents a general paracrine signaling mode, and how DLL4 signals are decoded differently across its diverse tissue contexts.
  • No high-resolution structure of DLL4-Notch complex in membrane context
  • Mechanism of DLL4 oscillation periodicity unresolved
  • Exosomal vs. soluble DLL4 signaling capacity not systematically compared

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005576 extracellular region 3 GO:0005886 plasma membrane 2 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1266738 Developmental Biology 4 R-HSA-168256 Immune System 4 R-HSA-1500931 Cell-Cell communication 2 R-HSA-1643685 Disease 2
Partners
FOXC2JAG1MPDZNECTIN2NOTCH1NOTCH3NOTCH4RHOQ

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 Jagged1 antagonizes DLL4-Notch signaling in endothelial cells expressing Fringe family glycosyltransferases; glycosylation of Notch enhances DLL4-Notch signaling whereas Jagged1 has weak signaling capacity and competes with DLL4, establishing opposing roles for the two ligands in angiogenesis. Genetic mouse models, in vivo angiogenesis assays, functional studies with Fringe glycosyltransferases Cell High 19524514
2006 Neutralizing DLL4 with a selective antibody renders endothelial cells hyperproliferative and causes defective cell fate specification/differentiation, demonstrating that DLL4-mediated Notch signaling regulates endothelial cell proliferation and differentiation and is crucial during active vascularization. Anti-DLL4 neutralizing antibody treatment, in vitro and in vivo endothelial cell assays, tumor models Nature High 17183323
2007 DLL4 expression is dynamically induced by VEGF in the retinal vasculature and acts as a negative feedback regulator to prevent overexuberant angiogenic sprouting; pharmacological inhibition of DLL4/Notch signaling (via soluble DLL4-Fc or blocking antibody) produces enhanced sprouting and increased endothelial proliferation. Intraocular administration of soluble DLL4-Fc and blocking antibody; Dll4 haploinsufficiency mouse model; postnatal retinal vascular analysis Proceedings of the National Academy of Sciences of the United States of America High 17296940
2003 VEGF, but not bFGF, induces DLL4 and Notch1 gene expression in human arterial endothelial cells via VEGFR1 and VEGFR2 through a PI3K/Akt pathway, independently of MAPK and Src; constitutive Notch activation stabilizes endothelial network formation. Gene expression analysis, pharmacological inhibitors of PI3K/Akt, MAPK, and Src; 3D angiogenesis model; Matrigel network formation assay Molecular and cellular biology High 12482957
2011 Simultaneous genetic inactivation of Dll1 and Dll4 in mouse intestinal epithelium causes complete conversion of proliferating progenitors into postmitotic goblet cells with loss of intestinal stem cells, establishing that DLL1 and DLL4 together are the physiological Notch ligands required for intestinal stem cell maintenance. Inducible gut-specific gene targeting (Vil-Cre-ERT2) in mice; single and double conditional knockouts; lineage analysis with Notch1 reporter Gastroenterology High 21238454
2017 Genetic experiments in postnatal mice reveal that the level of active Notch signaling (not direct DLL4-mediated cell-cell communication per se) is the key determinant of vessel growth; Notch activation directs tip-derived endothelial cells into developing arteries, coupling sprouting angiogenesis with artery formation. Endothelial VEGF-A and CXCR4 expression are key processes controlling Notch-dependent vessel growth. Endothelial-specific genetic targeting of Dll4 in tip cells in postnatal mice; conditional knockout models; retinal vascular analysis Nature cell biology High 28714968
2010 Endothelial-specific stabilization of Wnt/β-catenin signaling upregulates Dll4 transcription and strongly increases Notch signaling in the endothelium, linking Wnt and Notch signaling pathways in vascular development and arteriovenous specification. Endothelial-specific β-catenin gain-of-function mouse models; in vitro β-catenin activation; chromatin/transcriptional analysis of Dll4 promoter Developmental cell High 20627076
2008 Foxc1 and Foxc2 transcription factors directly activate the Dll4 promoter and the Notch target Hey2 promoter via Foxc binding elements; Foxc2 physically interacts with a Notch transcriptional activation complex (Su(H)/NICD) to induce Hey2 promoter activity; VEGF-activated PI3K and ERK pathways modulate Foxc transcriptional activity in Dll4 and Hey2 induction. Promoter reporter assays, co-immunoprecipitation, siRNA knockdown, VEGF stimulation with PI3K/ERK inhibitors in endothelial cells PloS one High 18545664
2013 Arterial Dll4 expression is regulated combinatorially by Notch signaling (via RBPJ/NICD direct binding) and SoxF transcription factors (Sox7, Sox18) through two arterial-specific enhancers; combinatorial loss of both SoxF and RBPJ binding ablates all Dll4 enhancer activity and results in loss of arterial markers and dorsal aorta. Arterial-specific enhancer characterization in mouse and zebrafish; transgenic reporter assays; combined Sox7/Sox18/Rbpj knockdown; endogenous dll4 expression analysis Proceedings of the National Academy of Sciences of the United States of America High 23818617
2006 Hypoxia induces DLL4 expression through HIF-1α, which leads to activation of Notch target genes Hey1 and Hey2; in endothelial progenitor cells, hypoxia-mediated upregulation of DLL4 and Hey2 represses COUP-TFII (a venous identity regulator), promoting arterial cell fate; Hey factors create a negative feedback on HIF-1α-induced gene expression. Promoter analysis, HIF-1α overexpression/knockdown, endothelial progenitor cell culture under hypoxia, reporter assays Experimental cell research Medium 17045587
2012 The microRNA-30 family directly targets the DLL4 3'UTR to repress DLL4 expression; miR-30b overexpression in endothelial cells increases vessel number/length in sprouting assays; microinjection of miR-30 mimics in zebrafish suppresses dll4 and causes excessive intersegmental vessel sprouting; target protector against the miR-30 site in dll4 3'UTR upregulates dll4. miRNA target site mutagenesis/target protector, overexpression in endothelial cells, zebrafish microinjection, sprouting angiogenesis assay Blood High 23086751
2015 DLL4 expression in intestinal lacteals requires VEGFR3 and VEGFR2 activation; genetic inactivation of Dll4 specifically in lymphatic endothelial cells leads to lacteal regression and impaired dietary fat uptake, establishing DLL4 as a regulator of adult lymphatic vessel maintenance and intestinal fat absorption. Lymphatic endothelial cell-specific Dll4 conditional knockout mice; VEGFR inhibition; dietary fat uptake assays; histological analysis The Journal of clinical investigation High 26529256
2015 DLL4 is expressed on bone marrow osteocalcin-positive (Ocn+) mesenchymal cells; selective depletion of DLL4 from these cells recapitulates thymopoietic abnormality (reduced thymus-seeding progenitors and T cell generation), establishing that bone marrow DLL4 drives thymus-seeding progenitor generation. In vivo deletion of DLL4 from Ocn+ cells; conditional cell-specific knockouts; progenitor frequency analysis; thymic function assays The Journal of experimental medicine High 25918341
2011 Notch1-Dll4 signaling regulates postnatal lymphatic development; antibody blockade of Notch1 and Dll4 results in defective lymphatic sprouting associated with downregulation of EphrinB2 (which mediates VEGFR3/VEGFC signaling), dilation of collecting lymphatics with reduced mural cell coverage, and impaired wound-associated lymphangiogenesis. Function-blocking antibodies against Notch1 and Dll4 in mice; EphrinB2 expression analysis; wound healing lymphangiogenesis model Blood High 21700774
2009 DLL4 expression in endothelial cells of the tumor microenvironment activates Notch3 signaling in co-cultured T-ALL tumor cells, promoting their escape from dormancy; neutralization of DLL4 greatly reduces EC-mediated Notch3 activation in T-ALL cells and blocks tumorigenesis. EC-tumor cell co-culture, angiogenic factor stimulation, DLL4 neutralization, Notch3 silencing by RNAi, in vivo tumorigenicity assays Cancer research Medium 19208840
2011 Adhesion of endothelial cells to laminin-111 via α2β1 and α6β1 integrins triggers DLL4 expression and subsequent Notch pathway activation; VEGF stimulates laminin γ1 deposition which leads to integrin signaling and DLL4 induction; loss of α2 or α6 integrins mimics Dll4 silencing and induces excessive network branching. siRNA knockdown of integrins and DLL4, laminin adhesion assays, 3D sprouting angiogenesis assay, signaling pathway analysis Circulation research Medium 21474814
2009 DLL4 is inducible on dendritic cells by TLR activation (not by early inflammatory cytokines IL-1/IL-18); DLL4 on DCs promotes IL-17-producing T cell generation via upregulation of Rorc expression; both Rorc and Il17 gene promoters are direct transcriptional Notch targets. In vitro DC-T cell co-culture with TLR ligands; Notch inhibition; Rorc and Il17 promoter analysis; cytokine measurements Journal of immunology Medium 19494260
2012 KSHV vGPCR upregulates DLL4 through an ERK-dependent mechanism in lymphatic endothelial cells; DLL4-stimulated Notch4 signaling suppresses cell cycle genes in neighboring lymphatic endothelial cells, inducing cellular quiescence. KSHV gene expression studies, ERK inhibition, NF-κB inhibition, gene expression profiling, functional Notch signaling assay PLoS pathogens Medium 19816565
2012 LRF (leukemia/lymphoma related factor) acts as an erythroid-specific repressor of Dll4 expression; Lrf deletion in erythroblasts upregulates Dll4, sensitizing HSCs to T-cell instructive Notch signals in the bone marrow, leading to premature lymphoid differentiation and loss of HSC maintenance. In vivo mouse models with erythroblast-specific Lrf deletion; functional HSC assays; Dll4 expression analysis in erythroblasts Blood High 23134786
2012 Dll4-Notch signaling between DN1 T cell progenitors and thymic DCs regulates thymic DC development and regulatory T cell homeostasis; pharmacological Dll4 blockade converts DN1 progenitors to immature DCs, which then expand Treg cells via a DC-dependent, MHC-II-dependent mechanism independent of Flt3. Anti-Dll4 antibody blockade; genetic inactivation models; thymectomy experiments; flow cytometry; DC-T cell co-culture The Journal of experimental medicine High 22547652
2015 Cerebral cavernous malformation protein CCM1 controls DLL4-Notch3 signaling between endothelial cells and pericytes; CCM1 silencing in endothelial cells decreases DLL4 levels, reducing Notch3 activity in co-cultured pericytes; DLL4 stimulates Notch3 on brain pericytes, inducing expression of PDGFRB2, N-Cadherin, HBEGF, TGFB1, NG2, and S1P, enhancing pericyte adhesion and antiangiogenic function. siRNA knockdown of CCM1 in endothelial cells; EC-pericyte co-culture; Notch3 reporter assays; transgenic Ccm1/Ccm2 endothelial knockout mouse models Stroke Medium 25791711
2016 Dll4 fluctuations in individual endothelial cells drive sprout branching through heterogeneous phase patterns; pathologically high VEGF or DLL4 overexpression leads to Notch-dependent synchronization of Dll4 fluctuations within endothelial clusters, switching vessels from branching to expansion mode. Live imaging of Dll4 expression in mouse retina in vivo and embryonic stem cell-derived sprouting assays; DLL4 overexpression; Notch inhibition eLife High 27074663
2018 The multiple PDZ domain protein MPDZ physically interacts with the intracellular C-terminus of DLL4 (and DLL1) and enables their interaction with the adherens junction protein Nectin-2; MPDZ inactivation leads to impaired DLL4-induced Notch signaling activity and increased blood vessel sprouting. Co-immunoprecipitation of MPDZ with DLL4 and Nectin-2; MPDZ gene inactivation in endothelial cells; Notch signaling reporter assays; embryonic mouse hindbrain vascular analysis eLife High 29620522
2019 LPA4 and LPA6 receptors activate YAP/TAZ through Gα12/Gα13-Rho-ROCK signaling in endothelial cells; YAP/TAZ knockdown increases β-catenin- and NICD-mediated DLL4 expression; the LPA4/LPA6-Gα12/Gα13-YAP/TAZ axis thereby represses endothelial DLL4 expression to promote sprouting angiogenesis. Endothelial-specific Lpa4;Lpa6 double KO mice; siRNA knockdown of signaling components; fibrin gel sprouting assay; Notch inhibitor rescue The Journal of clinical investigation High 31335323
2019 High glucose activates a DLL4-Notch1 positive feedback loop in keratinocytes; Notch1 inactivation specifically in keratinocytes cancels the repressive effects of this loop on wound healing in diabetes, demonstrating that keratinocyte-specific Dll4-Notch1 signaling impairs diabetic wound healing. Loss-of-function genetic approaches (keratinocyte-specific Notch1 knockout); diabetic mouse wound healing models; pharmacological Notch inhibition Proceedings of the National Academy of Sciences of the United States of America High 30886104
2019 Indoxyl sulfate induces DLL4 protein upregulation in macrophages (partly through inhibition of the ubiquitin-proteasome pathway via the deubiquitinating enzyme USP5); DLL4 then activates Notch signaling to drive proinflammatory macrophage polarization; the uptake pathway is mediated by OATP2B1 transporter; macrophage-specific DLL4 knockout inhibits atherosclerosis in Ldlr-/- mice. Global proteomics; siRNA knockdown via macrophage-targeted lipid nanoparticles; macrophage-specific DLL4 KO; atherosclerosis mouse model; Dll4 antibody treatment Circulation High 30586693
2020 Dll4 acts as a negative regulator of intra-aortic hematopoietic cluster (IAHC) formation by impairing the recruitment of surrounding hemogenic cells into existing clusters; blocking Dll4 promotes entry of new hemogenic Gfi1+ cells into IAHCs and increases HSC numbers. Live imaging of organotypic slice cultures; clonal analysis; mathematical modeling; Dll4 blocking experiments The EMBO journal High 32149421
2022 In skeletal muscle atrophy (disuse or diabetes), microvascular endothelium upregulates and releases DLL4, which activates muscular Notch2 without direct cell-cell contact; inhibition of the Dll4-Notch2 axis prevents muscle atrophy and promotes overloading-induced hypertrophy in mice. Mouse models of disuse and diabetic atrophy; Dll4-Notch2 axis inhibition; endothelial Dll4 overexpression; muscle mass/signaling analysis Nature metabolism High 35228746
2015 DLL4 is expressed on a sub-population of bipotent hematoendothelial progenitors (HEPs) in hESCs; DLL4-high HEPs are enriched in endothelial potential while DLL4-low/-negative HEPs are committed to hematopoietic lineage; DLL4 stimulation enhances hematopoietic differentiation of HEPs and increases clonogenic hematopoietic progenitor output. hESC differentiation; clonal analysis; transcriptome profiling; confocal imaging of embryoid bodies; DLL4 stimulation assays Leukemia Medium 25778099
2015 DLL4 only is an efficient cis-inhibitor of Notch signaling whereas DLL1 has minimal cis-inhibitory activity; this differential cis-inhibition property contributes to functional divergence of DLL1 and DLL4 in tissue-specific contexts, explaining why transgenic DLL4 cannot replace DLL1 during somitogenesis. Conditional overexpression from Hprt locus; knock-in of Dll4 into Dll1 locus (Dll1Dll4ki); in vitro cis/trans Notch activation assays PLoS genetics High 26114479
2018 TLR4 signaling in lung endothelial cells activates ERK phosphorylation, which causes ERK-dependent phosphorylation of FOXC2 and its transcriptional activation of the DLL4 gene; FOXC2-siRNA or ERK inhibition attenuates LPS-induced DLL4 expression and aberrant angiogenic sprouting both in vitro and in vivo. LPS stimulation of endothelial cells; pharmacological ERK inhibition; FOXC2 siRNA; ERK-2 dominant negative; FOXC2 ChIP at DLL4 promoter; neonatal mouse retinal angiogenesis model The Journal of physiology Medium 29380370
2020 RHOQ is induced by DLL4/Notch signaling and is essential for NICD nuclear translocation; in the absence of RHOQ, Notch1 is targeted for degradation in the autophagy pathway and NICD is sequestered from the nucleus and degraded in lysosomes, establishing a feed-forward mechanism. RHOQ siRNA knockdown; RHOQ overexpression; Notch signaling reporter assays; in vitro sprouting assay; zebrafish in vivo vascular analysis; subcellular localization studies Angiogenesis Medium 32506201
2014 Fibulin-3 activates ADAM10/17 in endothelial cells by inhibiting TIMP3, resulting in increased Notch cleavage and increased DLL4 expression independently of VEGF signaling; DLL4 knockdown reduces fibulin-3-dependent proangiogenic effects in vitro. ADAM10/17 inhibition; DLL4 siRNA knockdown; TIMP3 inhibition; endothelial cell motility and tubule formation assays; glioma xenograft models Cancer research Medium 25139440
2019 DLL4 in coronary arterial development functions within a Dll4-Jag1-EphrinB2 signaling cascade; Dll4 inactivation stimulates excessive capillary growth from sinus venosus, while forced Dll4 expression or Mfng overexpression blocks coronary plexus remodeling and arterial differentiation; EphrinB2 is a critical downstream effector of Dll4 in arterial morphogenesis. Endocardial-specific Jag1 and Dll4 conditional knockout mice; forced Dll4/Mfng expression; angiogenic rescue in ventricular explants and primary human ECs eLife High 31789590
2021 In zebrafish valvulogenesis, blood flow-induced shear stress activates Notch signaling in endocardial cells via Dll4-mediated lateral inhibition, singling out Dll4-positive endocardial cells that ingress into the cardiac jelly in response to Wnt9a (produced through Erk5-Klf2-Wnt9a cascade); these parallel mechanosensitive pathways produce binary luminal/abluminal cell fate decisions. Zebrafish genetic models; live imaging; Notch/Wnt9a pathway manipulation; endocardial cell fate analysis Cell reports Medium 34610316
2021 Pre-existing embryonic coronary plexus at the inner myocardium undergoes DLL4-NOTCH1 signaling-dependent angiogenic expansion to vascularize the expanding neonatal myocardium and to revascularize the regenerating neonatal heart. Lineage-tracing experiments; gain- and loss-of-function of Dll4-Notch1 in mice; live vascular imaging Nature cell biology High 34497373
2019 Soluble DLL4 activates Notch signaling in endothelial cells, increasing VE-cadherin at intercellular junctions and reducing vascular permeability through a cAMP/PKA-dependent pathway; PKA inhibition reverses DLL4-mediated barrier enhancement both in vitro and in vivo. Recombinant sDll4 treatment of EC monolayers; FITC-albumin permeability assay; γ-secretase inhibitor; PKA inhibition (H89); in vivo rat mesenteric microvessel hydraulic conductivity American journal of physiology. Heart and circulatory physiology Medium 30681366
2019 TMZ treatment promotes nuclear translocation of MMP14 followed by extracellular release of DLL4; secreted DLL4 stimulates cleavage of Notch3, its nuclear translocation, and induction of GBM stemness and sphere formation. MMP14 expression and localization analysis after TMZ treatment in PDX GBM models; Kiloplex ELISA-based protein array; DLL4 functional and mechanistic studies; sphering capacity assays International journal of cancer Medium 31443114
2023 Epsin1 modulates the sorting of DLL4 into tubular epithelial cell-derived exosomes under high-glucose conditions; exosomal DLL4 is captured by macrophages and promotes M1 macrophage activation via Notch1 (N1ICD) activation; Epsin1 knockdown in TECs reduces exosomal DLL4 and inhibits macrophage Notch1 activation. Mass spectrometry of urine exosomes; siRNA knockdown of Epsin1; TEC-macrophage co-culture with exosomes; in vivo mouse diabetic nephropathy model Molecular therapy Medium 37016580
2022 DLL4 binds human and murine Notch receptors; affinity-matured DLL4 variant (DeltaMAX) has 500- to 1,000-fold increased receptor-binding affinity; DeltaMAX acts as agonist in plate/bead-bound format and as antagonist (soluble decoy) in reporter and neuronal differentiation assays, demonstrating dose/format-dependent agonist/antagonist activity. In vitro binding affinity assays; Notch reporter assays; neuronal differentiation assays; T cell stimulation assays; directed evolution/affinity maturation Nature chemical biology High 36050494
2024 Palmitic acid induces macrophage DLL4 expression, which triggers senescence in vascular smooth muscle cells (reducing collagen synthesis/deposition); macrophage-specific DLL4 knockout in atherosclerotic mice reduces plaque burden and improves plaque stability. Human cohort correlation; macrophage-specific DLL4 conditional KO in atherosclerotic mouse models; vascular smooth muscle cell senescence assays Nature communications High 38346959
2015 Heterozygous loss-of-function mutations (nonsense and missense, including cysteine-altering variants) in DLL4 cause autosomal-dominant Adams-Oliver syndrome, establishing DLL4 as an essential Notch ligand for vascular development in humans. Targeted resequencing of DLL4 in 89 AOS families; whole-exome/genome sequencing; candidate gene approach based on known DLL4 function American journal of human genetics Medium 26299364
2018 DLL4 signaling via Notch1 impairs M2 macrophage differentiation and induces caspase3/7-dependent apoptosis selectively during M2 (but not M1) macrophage polarization; DLL4 upregulates pro-apoptotic effectors Bax, Bak, Bid, and Bim; fully differentiated M2 macrophages become resistant to DLL4 action. Human monocyte differentiation in vitro with immobilized recombinant DLL4; flow cytometry; qPCR; western blot for apoptotic pathway components; Notch inhibitors Cell communication and signaling Medium 29321062
2016 Endothelial DLL4 induces macrophage polarization into a proinflammatory M1 fate and elicits IL-6 production; both DLL4 and IL-6 are Notch-dependent and required for macrophage polarization; DLL4 upregulates M1-type markers and downregulates M2-type markers via Notch signaling in cardiac transplant rejection. EC/monocyte co-culture; endomyocardial biopsy analysis; flow cytometry; Notch signaling analysis Biochemical pharmacology Medium 26826491
2020 Slug (SNAI2) suppresses Dll4-Notch signaling in endothelial cells to promote VEGFR2 expression; EC-specific Slug re-expression or loss of Dll4 rescues retinal angiogenesis in SlugKO mice; endothelial Slug is activated by SDF1α via CXCR4-ERK5 signaling. Slug endothelial-specific KO mice; Dll4 loss-of-function rescue; γ-secretase inhibition rescue; VEGF signaling inhibition; Notch target gene analysis Nature communications High 33106502

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell 889 19524514
2006 Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 790 17183323
2007 Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proceedings of the National Academy of Sciences of the United States of America 609 17296940
2003 Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Molecular and cellular biology 414 12482957
2011 Dll1- and dll4-mediated notch signaling are required for homeostasis of intestinal stem cells. Gastroenterology 350 21238454
2017 Dll4 and Notch signalling couples sprouting angiogenesis and artery formation. Nature cell biology 324 28714968
2009 DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell stem cell 322 19664991
2010 The Wnt/beta-catenin pathway modulates vascular remodeling and specification by upregulating Dll4/Notch signaling. Developmental cell 264 20627076
2007 Regulation of multiple angiogenic pathways by Dll4 and Notch in human umbilical vein endothelial cells. Microvascular research 182 17692341
2006 Hypoxia-mediated activation of Dll4-Notch-Hey2 signaling in endothelial progenitor cells and adoption of arterial cell fate. Experimental cell research 177 17045587
2019 Uremic Toxin Indoxyl Sulfate Promotes Proinflammatory Macrophage Activation Via the Interplay of OATP2B1 and Dll4-Notch Signaling. Circulation 173 30586693
2009 Regulation of T cell activation by Notch ligand, DLL4, promotes IL-17 production and Rorc activation. Journal of immunology (Baltimore, Md. : 1950) 154 19494260
2012 The microRNA-30 family targets DLL4 to modulate endothelial cell behavior during angiogenesis. Blood 151 23086751
2015 DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport. The Journal of clinical investigation 145 26529256
2008 Foxc transcription factors directly regulate Dll4 and Hey2 expression by interacting with the VEGF-Notch signaling pathways in endothelial cells. PloS one 142 18545664
2015 Specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow. The Journal of experimental medicine 128 25918341
2009 Cross-talk between tumor and endothelial cells involving the Notch3-Dll4 interaction marks escape from tumor dormancy. Cancer research 125 19208840
2013 Analysis of Dll4 regulation reveals a combinatorial role for Sox and Notch in arterial development. Proceedings of the National Academy of Sciences of the United States of America 110 23818617
2015 Endothelial Jagged1 antagonizes Dll4 regulation of endothelial branching and promotes vascular maturation downstream of Dll4/Notch1. Arteriosclerosis, thrombosis, and vascular biology 106 25767274
2010 Anti-DLL4 inhibits growth and reduces tumor-initiating cell frequency in colorectal tumors with oncogenic KRAS mutations. Cancer research 96 21193546
2011 Laminin-binding integrins induce Dll4 expression and Notch signaling in endothelial cells. Circulation research 95 21474814
2009 Expression of delta-like ligand 4 (Dll4) and markers of hypoxia in colon cancer. British journal of cancer 95 19844231
2019 Lysophosphatidic acid-induced YAP/TAZ activation promotes developmental angiogenesis by repressing Notch ligand Dll4. The Journal of clinical investigation 93 31335323
2016 Synchronization of endothelial Dll4-Notch dynamics switch blood vessels from branching to expansion. eLife 93 27074663
2020 Slug regulates the Dll4-Notch-VEGFR2 axis to control endothelial cell activation and angiogenesis. Nature communications 86 33106502
2018 Notch signaling triggered via the ligand DLL4 impedes M2 macrophage differentiation and promotes their apoptosis. Cell communication and signaling : CCS 82 29321062
2011 The Notch1-Dll4 signaling pathway regulates mouse postnatal lymphatic development. Blood 80 21700774
2019 Triggering of a Dll4-Notch1 loop impairs wound healing in diabetes. Proceedings of the National Academy of Sciences of the United States of America 75 30886104
2015 Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome. American journal of human genetics 75 26299364
2010 Combination of Dll4/Notch and Ephrin-B2/EphB4 targeted therapy is highly effective in disrupting tumor angiogenesis. BMC cancer 74 21092311
2018 A first-in-human phase 1a study of the bispecific anti-DLL4/anti-VEGF antibody navicixizumab (OMP-305B83) in patients with previously treated solid tumors. Investigational new drugs 65 30229512
2011 Influence of Dll4 via HIF-1α-VEGF signaling on the angiogenesis of choroidal neovascularization under hypoxic conditions. PloS one 64 21526177
2015 Cerebral Cavernous Malformation-1 Protein Controls DLL4-Notch3 Signaling Between the Endothelium and Pericytes. Stroke 63 25791711
2006 Expression of Dll4 and CCL25 in Foxn1-negative epithelial cells in the post-natal thymus. International immunology 59 17158094
2012 Anti-DLL4 has broad spectrum activity in pancreatic cancer dependent on targeting DLL4-Notch signaling in both tumor and vasculature cells. Clinical cancer research : an official journal of the American Association for Cancer Research 54 22952347
2020 Crenigacestat, a selective NOTCH1 inhibitor, reduces intrahepatic cholangiocarcinoma progression by blocking VEGFA/DLL4/MMP13 axis. Cell death and differentiation 53 32042099
2019 Delta-like ligand 4/DLL4 regulates the capillarization of liver sinusoidal endothelial cell and liver fibrogenesis. Biochimica et biophysica acta. Molecular cell research 53 31233801
2013 Implications of Dll4-Notch signaling activation in primary glioblastoma multiforme. Neuro-oncology 51 23787764
2012 Cross-talk between leukemic and endothelial cells promotes angiogenesis by VEGF activation of the Notch/Dll4 pathway. Carcinogenesis 51 23239744
2009 KSHV manipulates Notch signaling by DLL4 and JAG1 to alter cell cycle genes in lymphatic endothelia. PLoS pathogens 51 19816565
2012 MEDI0639: a novel therapeutic antibody targeting Dll4 modulates endothelial cell function and angiogenesis in vivo. Molecular cancer therapeutics 48 22679110
2016 Notch signaling mediates crosstalk between endothelial cells and macrophages via Dll4 and IL6 in cardiac microvascular inflammation. Biochemical pharmacology 47 26826491
2015 The Notch ligand DLL4 specifically marks human hematoendothelial progenitors and regulates their hematopoietic fate. Leukemia 47 25778099
2012 Dll4-Fc, an inhibitor of Dll4-notch signaling, suppresses liver metastasis of small cell lung cancer cells through the downregulation of the NF-κB activity. Molecular cancer therapeutics 47 22989420
2014 Dll4 blockade potentiates the anti-tumor effects of VEGF inhibition in renal cell carcinoma patient-derived xenografts. PloS one 46 25393540
2020 Notch ligand Dll4 impairs cell recruitment to aortic clusters and limits blood stem cell generation. The EMBO journal 45 32149421
2008 Dll4 activation of Notch signaling reduces tumor vascularity and inhibits tumor growth. Blood 45 18577711
2013 Down-Regulated miR-30a in Clear Cell Renal Cell Carcinoma Correlated with Tumor Hematogenous Metastasis by Targeting Angiogenesis-Specific DLL4. PloS one 44 23826258
2012 LRF-mediated Dll4 repression in erythroblasts is necessary for hematopoietic stem cell maintenance. Blood 43 23134786
2012 Dll4-Notch signaling in Flt3-independent dendritic cell development and autoimmunity in mice. The Journal of experimental medicine 42 22547652
2022 The endothelial Dll4-muscular Notch2 axis regulates skeletal muscle mass. Nature metabolism 40 35228746
2014 Novel paracrine modulation of Notch-DLL4 signaling by fibulin-3 promotes angiogenesis in high-grade gliomas. Cancer research 39 25139440
2013 Association of Dll4/notch and HIF-1a -VEGF signaling in the angiogenesis of missed abortion. PloS one 38 23950980
2015 MMGZ01, an anti-DLL4 monoclonal antibody, promotes nonfunctional vessels and inhibits breast tumor growth. Cancer letters 37 26739060
2014 DLL4 regulates NOTCH signaling and growth of T acute lymphoblastic leukemia cells in NOD/SCID mice. Carcinogenesis 35 25355291
2023 Epsin1-mediated exosomal sorting of Dll4 modulates the tubular-macrophage crosstalk in diabetic nephropathy. Molecular therapy : the journal of the American Society of Gene Therapy 34 37016580
2018 ABT-165, a Dual Variable Domain Immunoglobulin (DVD-Ig) Targeting DLL4 and VEGF, Demonstrates Superior Efficacy and Favorable Safety Profiles in Preclinical Models. Molecular cancer therapeutics 34 29592882
2018 MPDZ promotes DLL4-induced Notch signaling during angiogenesis. eLife 34 29620522
2016 Simultaneous blockade of VEGF and Dll4 by HD105, a bispecific antibody, inhibits tumor progression and angiogenesis. mAbs 34 27049350
2015 Context-Dependent Functional Divergence of the Notch Ligands DLL1 and DLL4 In Vivo. PLoS genetics 34 26114479
2022 DLL4 and VCAM1 enhance the emergence of T cell-competent hematopoietic progenitors from human pluripotent stem cells. Science advances 32 36001668
2021 Mechanosensitive Notch-Dll4 and Klf2-Wnt9 signaling pathways intersect in guiding valvulogenesis in zebrafish. Cell reports 32 34610316
2024 Palmitic acid in type 2 diabetes mellitus promotes atherosclerotic plaque vulnerability via macrophage Dll4 signaling. Nature communications 31 38346959
2021 Perinatal angiogenesis from pre-existing coronary vessels via DLL4-NOTCH1 signalling. Nature cell biology 31 34497373
2014 Endothelial Delta-like 4 (DLL4) promotes renal cell carcinoma hematogenous metastasis. Oncotarget 31 24931473
2020 ABL001, a Bispecific Antibody Targeting VEGF and DLL4, with Chemotherapy, Synergistically Inhibits Tumor Progression in Xenograft Models. International journal of molecular sciences 30 33383646
2019 Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells. Oncogene 30 31616059
2016 Arterialization and anomalous vein wall remodeling in varicose veins is associated with upregulated FoxC2-Dll4 pathway. Laboratory investigation; a journal of technical methods and pathology 30 26808710
2019 Coronary arterial development is regulated by a Dll4-Jag1-EphrinB2 signaling cascade. eLife 29 31789590
2018 Endothelial immune activation programmes cell-fate decisions and angiogenesis by inducing angiogenesis regulator DLL4 through TLR4-ERK-FOXC2 signalling. The Journal of physiology 29 29380370
2019 Activation of Notch signaling by soluble Dll4 decreases vascular permeability via a cAMP/PKA-dependent pathway. American journal of physiology. Heart and circulatory physiology 28 30681366
2018 Inhibition of Dll4/Notch1 pathway promotes angiogenesis of Masquelet's induced membrane in rats. Experimental & molecular medicine 28 29674611
2015 Cyclic AMP Response Element Binding Protein Mediates Pathological Retinal Neovascularization via Modulating DLL4-NOTCH1 Signaling. EBioMedicine 27 26870802
2020 DLL1- and DLL4-Mediated Notch Signaling Is Essential for Adult Pancreatic Islet Homeostasis. Diabetes 26 32029480
2020 Highly Expressed DLL4 and JAG1: Their Role in Incidence of Breast Cancer Metastasis. Archives of medical research 26 32111499
2016 A humanized anti-DLL4 antibody promotes dysfunctional angiogenesis and inhibits breast tumor growth. Scientific reports 26 27301650
2021 Substrate stiffness modulates endothelial cell function via the YAP-Dll4-Notch1 pathway. Experimental cell research 25 34543658
2015 HDAC5 promotes colorectal cancer cell proliferation by up-regulating DLL4 expression. International journal of clinical and experimental medicine 25 26131280
2013 Clinical implications of DLL4 expression in gastric cancer. Journal of experimental & clinical cancer research : CR 25 23898884
2016 DLL4+ dendritic cells: Key regulators of Notch Signaling in effector T cell responses. Pharmacological research 24 27639599
2020 RHOQ is induced by DLL4 and regulates angiogenesis by determining the intracellular route of the Notch intracellular domain. Angiogenesis 23 32506201
2018 Propranolol inhibits proliferation and invasion of hemangioma-derived endothelial cells by suppressing the DLL4/Notch1/Akt pathway. Chemico-biological interactions 23 30130526
2024 LRP1 induces anti-PD-1 resistance by modulating the DLL4-NOTCH2-CCL2 axis and redirecting M2-like macrophage polarisation in bladder cancer. Cancer letters 22 38462037
2021 Nestin+/CD31+ cells in the hypoxic perivascular niche regulate glioblastoma chemoresistance by upregulating JAG1 and DLL4. Neuro-oncology 22 33249476
2019 TMZ regulates GBM stemness via MMP14-DLL4-Notch3 pathway. International journal of cancer 22 31443114
2017 Notch Ligand DLL4 Alleviates Allergic Airway Inflammation via Induction of a Homeostatic Regulatory Pathway. Scientific reports 22 28262821
2015 Balancing Efficacy and Safety of an Anti-DLL4 Antibody through Pharmacokinetic Modulation. Clinical cancer research : an official journal of the American Association for Cancer Research 22 26589434
2020 TRIM28 regulates sprouting angiogenesis through VEGFR-DLL4-Notch signaling circuit. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 21 32918765
2019 Vascular endothelial growth factor 165 inhibits pro-fibrotic differentiation of stromal cells via the DLL4/Notch4/smad7 pathway. Cell death & disease 21 31515487
2018 Matrine blocks AGEs- induced HCSMCs phenotypic conversion via suppressing Dll4-Notch pathway. European journal of pharmacology 21 30063915
2017 Endothelial Dll4 overexpression reduces vascular response and inhibits tumor growth and metastasization in vivo. BMC cancer 21 28288569
2015 The vascular delta-like ligand-4 (DLL4)-Notch4 signaling correlates with angiogenesis in primary glioblastoma: an immunohistochemical study. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 21 26472724
2011 Role of the DLL4-NOTCH system in PGF2alpha-induced luteolysis in the pregnant rat. Biology of reproduction 21 21209419
2020 DR-5 and DLL-4 mAb Functionalized SLNs of Gamma-Secretase Inhibitors- An Approach for TNBC Treatment. Advanced pharmaceutical bulletin 19 34888208
2019 The bispecific antibody HB-32, blockade of both VEGF and DLL4 shows potent anti-angiogenic activity in vitro and anti-tumor activity in breast cancer xenograft models. Experimental cell research 19 31034805
2016 Activation of Dll4/Notch Signaling and Hypoxia-Inducible Factor-1 Alpha Facilitates Lymphangiogenesis in Lacrimal Glands in Dry Eye. PloS one 19 26828208
2012 Inhibition of Notch signaling by Dll4-Fc promotes reperfusion of acutely ischemic tissues. Biochemical and biophysical research communications 19 22252294
2011 Correlation of Delta-like ligand 4 (DLL4) with VEGF and HIF-1α expression in human glioma. Asian Pacific journal of cancer prevention : APJCP 19 21517260
2022 Engineered patterns of Notch ligands Jag1 and Dll4 elicit differential spatial control of endothelial sprouting. iScience 18 35602952
2022 Affinity-matured DLL4 ligands as broad-spectrum modulators of Notch signaling. Nature chemical biology 17 36050494