RGD Reference Report - Inhibition of delta-like-4-mediated signaling impairs reparative angiogenesis after ischemia. - Rat Genome Database

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

Authors: Al Haj Zen, Ayman  Oikawa, Atsuhiko  Bazan-Peregrino, Miriam  Meloni, Marco  Emanueli, Costanza  Madeddu, Paolo 
Citation: Al Haj Zen A, etal., Circ Res. 2010 Jul 23;107(2):283-93. doi: 10.1161/CIRCRESAHA.110.221663. Epub 2010 May 27.
RGD ID: 155641249
Pubmed: PMID:20508179   (View Abstract at PubMed)
PMCID: PMC2917749   (View Article at PubMed Central)
DOI: DOI:10.1161/CIRCRESAHA.110.221663   (Journal Full-text)


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-alpha-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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
limb ischemia exacerbatesISODll4 (Mus musculus)155641249; 155641249 RGD 
limb ischemia exacerbatesIMP 155641249 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Dll4  (delta like canonical Notch ligand 4)

Genes (Mus musculus)
Dll4  (delta like canonical Notch ligand 4)

Genes (Homo sapiens)
DLL4  (delta like canonical Notch ligand 4)


Additional Information