Cited by 80Angiogenesis and VEGF in CancerDevelopmental Biology and Gene RegulationLymphatic System and Diseases

Inhibition of delta-like-4-mediated signaling impairs reparative angiogenesis after ischemia

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Al Haj Zen, Ayman, Oikawa, Atsuhiko, Bazan-Peregrino, Miriam, Meloni, Marco, Emanueli, Costanza, Madeddu, Paolo·2010·Circulation Research

Abstract

Rationale : Notch signaling regulates vascular development. However, the implication of the Notch ligand Delta-like 4 (Dll4) in postischemic angiogenesis remains unclear. Objective : We investigated the role of Dll4/Notch signaling in reparative angiogenesis using a mouse model of ischemia. Methods and Results : We found Dll4 weakly expressed in microvascular endothelial cells of normoperfused muscles. Conversely, Dll4 is upregulated following ischemia and localized at the forefront of sprouting capillaries. We analyzed the effect of inhibiting endogenous Dll4 by intramuscular injection of an adenovirus encoding the soluble form of Dll4 extracellular domain ( Ad-sDll4 ). Dll4 inhibition caused the formation of a disorganized, low-perfused capillary network in ischemic muscles. This structural abnormality was associated to delayed blood flow recovery and muscle hypoxia and degeneration. Analysis of microvasculature at early stages of repair revealed that Dll4 inhibition enhances capillary sprouting in a chaotic fashion and causes excessive leukocyte infiltration of ischemic muscles. Furthermore, Dll4 inhibition potentiated the elevation of the leukocyte chemoattractant CXCL1 (chemokine [C-X-C motif] ligand 1) following ischemia, without altering peripheral blood levels of stromal cell–derived factor-1 and monocyte chemoattractant protein-1. In cultured human monocytes, Dll4 induces the transcription of Notch target gene Hes-1 and inhibits the basal and tumor necrosis factor-α–stimulated production of interleukin-8, the human functional homolog of murine CXCL1. The inhibitory effect of Dll4 on interleukin-8 was abolished by DAPT, a Notch inhibitor, or by coculturing activated human monocytes with Ad-sDll4 –infected endothelial cells. Conclusions : Dll4/Notch interaction is essential for proper reparative angiogenesis. Moreover, Dll4/Notch signaling regulates sprouting angiogenesis and coordinates the interaction between inflammation and angiogenesis under ischemic conditions.

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Crossref · 10.1161/circresaha.110.221663

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Authors
Al Haj Zen, A., Oikawa, A., Bazan-Peregrino, M., Meloni, M., Emanueli, C., & Madeddu, P.
Affiliations
  • From the Experimental Cardiovascular Medicine Division (A.A.H.Z., A.O., M.M., C.E., P.M.), Bristol Heart Institute, University of Bristol; and Institute of Biomedical Engineering (M.B.-P.), University of Oxford, United Kingdom. Present address for A.A.H.Z.: Cardiovascular Medicine Department, Wellcome Trust Centre for Human Genetics, University of Oxford, United Kingdom.
  • Centre for Human Genetics (GB)
Venue
Circulation Research
Published
2010-07-23
Volume
107
Issue
2
Pages
283-293
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
OpenAlex
W2121336222
Cited by
80
References
35
Citations by year
2024: 5 · 2023: 4 · 2022: 6 · 2021: 2 · 2020: 1 · 2019: 5 · 2018: 3 · 2017: 6 · 2016: 7 · 2015: 6 · 2014: 2 · 2013: 13 · 2012: 13
FWCI
4.30
Type
journal article
Language
en
Open access
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
  • Bristol Research (University of Bristol) (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
  • Explore Bristol Research (submittedVersion)
Funders
British Heart Foundation (PG/06/035/20641)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
Keywords
DLL4, Notch signaling, ischemia, capillary sprouting, muscle ischemia, leukocyte infiltration, CXCL1, interleukin-8, Hes1, microvascular endothelial cells, blood flow recovery
MeSH terms
Animals, Calcium-Binding Proteins, Cells, Cultured, Chemotaxis, Leukocyte, Disease Models, Animal, Hindlimb, Humans, Ischemia, Leukocytes, Male, Regeneration, Regional Blood Flow, Time Factors, Transfection, Ultrasonography, Signal Transduction, Interleukin-8, Laser-Doppler Flowmetry, Muscle, Skeletal, Neovascularization, Physiologic, Coculture Techniques, Intercellular Signaling Peptides and Proteins, Endothelial Cells, Adaptor Proteins, Signal Transducing, Mice, Receptors, Notch, Chemokine CXCL1

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